Note: Descriptions are shown in the official language in which they were submitted.
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1-'2-(4-HYDROXYPHENYL)-2-HYDROXYETHYL!-PIPERIDIN-4-OL COMPOUNDS AS NMDA
RECEPTOR
ANTAGONISTS
Technical Field
This invention relates to novel 3,4-dihydroquinolin-2(lI~-one compounds.
These compounds are useful as antagonists of NMDA (N-methyl-D-aspartate)
NR2B receptor, and are thus useful for the treatment of pain, stroke,
traumatic brain
injury, Parkinson's disease, Alzheimer's disease, depression, anxiety,
migraine, or
the like in mammalian, especially humans. The present invention also relates
to a
pharmaceutical composition comprising the above compounds.
Background Art
Glutamate plays dual role in the central nervous system (CNS) as essential
amino acid and the principal excitatory neurotransmitters. There are at least
four
classes of receptors, specifically N-methyl-aspartate (NMDA), 2-amino-3-
(methyl-
3-hydroxyisoxazol-4-yl)propionic acid (AMPA), kainate and metabotropic. ~
There
is considerable preclinical evidence that hyperalgesia and allodynia following
peripheral tissue or nerve injury is not only due to an increase in the
sensitivity of
primary afferent nociceptors at the site of injury but also depends on NMDA
receptor-mediated central changes in synaptic excitability. In humans, NMDA
receptor antagonists have also been found to decrease both pain perception and
sensitization. Also, overactivation of NMDA receptor is a key event for
triggering
neuronal cell death under pathological conditions of acute and chronic forms
of
neurodegeneration. However, while NMDA receptor inhibition has therapeutic
utility in the treatment of pain and neurodegenerative diseases, there are
significant
liabilities to many available NMDA receptor antagonists that can cause
potentially
serious side effects. NMDA subunits are differentially distributed in the CNS.
Especially, NR2B is believed to be restricted to the forebrain and laminas I
and II of
the dosal horn. The more discrete distribution of NR2B subunit in the CNS may
support a reduced side-effect profile of agents that act selectively at this
site.
For example, NMDA NR2B selective antagonists may have clinical utility
for the treatment of neuropathic and other pain conditions in human with a
reduced
side-effect profile than existing NMDA antagonists (S. Boyce, et al.,
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Neuropharmacology, 38, pp.611-623 (1999)).
International Publication Number WO 96/06081 discloses a variety of
phenol compounds. Especially, a compound represented by the following formula
is disclosed in it:
However, the known compounds have potential to prolong the QT-interval
due to their potent inhibitory activity at HERG (human ether-a-go-go related
gene)
potassium channel. QT prolongation is known to have a potential liability to
produce fatal cardiac arrhythmias of Torsades de Pointes (TdP) . The ability
to
prolong the cardiac action potential duration was identified as being due to
an
action at the HERD potassium channel. For example, drugs withdrawn from the
market due to QT prolongation, such as Cisapride and Terfenadine, are known to
be
potent HERG potassium channel blocker (Expert Opinion of Pharmacotherapy.; 2,
pp947-973, 2000). Therefore, it would be desirable if there were provided a
novel
NMDA NR2B selective antagonist with analgesic activity by systemic
administration and with reduced inhibitory activity at HERD potassium channel.
Brief Disclosure of the Invention
It has now surprisingly been found that phenol compounds of present
invention are NMDA NR2B selective antagonists with analgesic activity by
systemic administration and with reduced inhibitory activity at HERG channel.
Inhibitory activity at HERG channel was estimated from affinity for HERG type
potassium channel was investigated by checking [3H]dofetilide binding, which
can
predict inhibitory activity at HERG channel (Eur. J. Pharmacol., 430, pp147-
148,
2001). Selected compounds with low [3H]dofetilide binding activity were
evaluated in IHERG assay to check activity at HERG channel. The compounds of
the present invention show a reduced QT prolongation by removing a methyl
group
from the carbon atom adjacent to nitrogen atom on piperidine ring of the
formula (I).
Compound A
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The present invention provides a compound of the following formula (~:
R3
(
wherein R1 and R2 independently represents a hydrogen atom, a halogen atom or
an
alkyl group having from 1 to 6 carbon atoms;
R3 represents an aryl group having from 6 to 10 ring carbon atoms or a
heteroaryl
group having from 5 to 10 ring atoms which consists of from 1 to 4 heteroatoms
independently selected from the group consisting of sulfur atoms, oxygen atoms
and
nitrogen atoms;
said aryl groups having from 6 to 10 ring carbon atoms and said heteroaryl
groups
having from 5 to 10 atoms are unsubstituted or are substituted by at least one
substituent selected from the group consisting of substituents oc;
said substituents a are selected from the group consisting of halogen atoms,
alkyl
groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6
carbon
atoms or alkoxyalkyl groups having from 1 to 6 carbon atoms;
or a pharmaceutically acceptable ester of such compound,
or a pharmaceutically acceptable salt thereof.
The phenol compounds of this invention have an antagonistic action
towards NMDA NR2B receptor subtype selectively and are thus useful in
therapeutics, particularly for the treatment of stroke or brain injury,
chronic
neurodegenerative disease such as Parkinson's disease, Alzheimer's disease,
Huntington's disease or amyotrophic lateral sclerosis (ALS), epilepsy,
convulsive
disorder, pain, anxiety, human immunodeficiency virus (HIV) related neuronal
injury, migraine, depression, schizophrenia, tumor, post-anesthesia cognitive
decline
(PACD), glaucoma, tinnitus, tradive dyskinesia, allergic encephalomyelitis,
opioid
tolerance, drug abuse, alcohol abuse, Irritable bowel syndrome (IBS), or the
like in
mammalian, especially humans.
The compounds of the present invention are useful for the general
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treatment of pain, particularly neuropathic pain. Physiological pain is an
important
protective mechanism designed to warn of danger from potentially injurious
stimuli
from the external environment. The system operates through a specific set of
primary sensory neurons and is exclusively activated by noxious stimuli via
peripheral transducing mechanisms (Millan 1999 Prog. Neurobio. 57: 1-164 for
an
integrative Review). These sensory fibres are known as nociceptors and are
characterized by small diameter axons with slow conduction velocities.
Nociceptors encode the intensity, duration and quality of noxious stimulus and
by
virtue of their topographically organized projection to the spinal cord, the
location of
the stimulus. The nociceptors are found on nociceptive nerve fibres of which
there
are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated).
The
activity generated by nociceptor input is transferred after complex processing
in the
dorsal horn, either directly or via brain stem relay nuclei to the ventrobasal
thalamus
and then on to the cortex, where the sensation of pain is generated.
Intense acute pain and chronic pain may involve the same pathways
driven by pathophysiological processes and as such cease to provide a
protective
mechanism and instead contribute to debilitating symptoms associated with a
wide
range of disease states. Pain is a feature of many trauma and disease states.
When
a substantial injury, via disease or trauma, to body tissue occurs the
characteristics of
nociceptor activation are altered. There is sensitisation in the periphery,
locally
around the injury and centrally where the nociceptors terminate. This leads to
hypersensitivity at the site of damage and in nearby normal tissue. In acute
pain
these mechanisms can be useful and allow for the repair processes to take
place and
the hypersensitivity returns to normal once the injury has healed. However, in
many chronic pain states, the hypersensitivity far outlasts the healing
process and is
normally due to nervous system injury. This injury often leads to
maladaptation of
the afferent fibres (Woolf & Salter 2000 Science 288: 1765-1768). Clinical
pain is
present when discomfort and abnormal sensitivity feature among the patient's
symptoms. Patients tend to be quite heterogeneous and may present with various
pain symptoms. There are a number of typical pain subtypes: 1) spontaneous
pain
which may be dull, burning, or stabbing; 2) pain responses to noxious stimuli
are
exaggerated (hyperalgesia); 3) pain is produced by normally innocuous stimuli
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(allodynia) (Meyer et al., 1994 Textbook of Pain 13-44). Although patients
with
back pain, arthritis pain, CNS trauma, or neuropathic pain may have similar
symptoms, the underlying mechanisms are different and, therefore, may require
different treatment strategies. Therefore pain can be divided into a number of
5 different areas because of differing pathophysiology, these include
nociceptive,
inflammatory, neuropathic pain etc. It should be noted that some types of pain
have multiple aetiologies and thus can be classified in more than one area,
e.g. Back
pain, Cancer pain have both nociceptive and neuropathic components.
Nociceptive pain is induced by tissue injury or by intense stimuli with the
potential to cause injury. Pain afferents are activated by transduction of
stimuli by
nociceptors at the site of injury and sensitise the spinal cord at the level
of their
termination. This is then relayed up the spinal tracts to the brain where pain
is
perceived (Meyer et al., 1994 Textbook of Pain 13-44). The activation of
nociceptors activates two types of afferent nerve fibres. Myelinated A-delta
fibres
transmitted rapidly and are responsible for the sharp and stabbing pain
sensations,
whilst unmyelinated C fibres transmit at a slower rate and convey the dull or
aching
pain. Moderate to severe acute nociceptive pain is a prominent feature of, but
is not
limited to pain from strains/sprains, post-operative pain (pain following any
type of
surgical procedure), posttraumatic pain, burns, myocardial infarction, acute
pancreatitis, and renal colic. Also cancer related acute pain syndromes
commonly
due to therapeutic interactions such as chemotherapy toxicity, immunotherapy,
hormonal therapy and radiotherapy. Moderate to severe acute nociceptive pain
is a
prominent feature of, but is not limited to, cancer pain which may be tumour
related
pain, (e.g. bone pain, headache and facial pain, viscera pain) or associated
with
cancer therapy (e.g. postchemotherapy syndromes, chronic postsurgical pain
syndromes, post radiation syndromes), back pain which may be due to herniated
or
ruptured intervertabral discs or abnormalities of the lumber facet joints,
sacroiliac
joints, paraspinal muscles or the posterior longitudinal ligament.
Neuropathic pain is defined as pain initiated or caused by a primary lesion
or dysfunction in the nervous system (IASP definition). Nerve damage can be
caused by trauma and disease and thus the term 'neuropathic pain' encompasses
many disorders with diverse aetiologies. These include but are not limited to,
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Diabetic neuropathy, Post herpetic neuralgia, Back pain, Cancer neuropathy,
HIV
neuropathy, Phantom limb pain, Carpal Tunnel Syndrome, chronic alcoholism,
hypothyroidism, trigeminal neuralgia, uremia, or vitamin deficiencies.
Neuropathic
pain is pathological as it has no protective role. It is often present well
after the
original cause has dissipated, commonly lasting for years, significantly
decreasing a
patients quality of life (Woolf and Mannion 1999 Lancet 353: 1959-1964). The
symptoms of neuropathic pain are difficult to treat, as they are often
heterogeneous
even between patients with the same disease (Woolf & Decosterd 1999 Pain Supp.
6: S 141-S 147; Woolf and Mannion 1999 Lancet 353: 1959-1964). They include
spontaneous pain, which can be continuous, or paroxysmal and abnormal evoked
pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and
allodynia
(sensitivity to a normally innocuous stimulus).
The inflammatory process is a complex series of biochemical and cellular
events activated in response to tissue injury or the presence of foreign
substances,
which result in swelling and pain (Levine and Taiwo 1994: Textbook of Pain 45-
56).
Arthritic pain makes up the majority of the inflammatory pain population.
Rheumatoid disease is one of the commonest chronic inflammatory conditions in
developed countries and rheumatoid arthritis is a common cause of disability.
The
exact aetiology of RA is unknown, but current hypotheses suggest that both
genetic
and microbiological factors may be important (Grennan & Jayson 1994 Textbook
of
Pain 397-407). It has been estimated that almost 16 million Americans have
symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom
are
over 60 years of age, and this is expected to increase to 40 million as the
age of the
population increases, making this a public health problem of enormous
magnitude
(Houge & Mersfelder 2002 Ann Pharmacother. 36: 679-686; McCarthy et al., 1994
Textbook of Pain 387-395). Most patients with OA seek medical attention
because
of pain. Arthritis has a significant impact on psychosocial and physical
function
and is known to be the leading cause of disability in later life. Other types
of
inflammatory pain include but are not limited to inflammatory bowel diseases
(IBD),
Other types of pain include but are not limited to;
- Musculo-skeletal disorders including but not limited to myalgia,
fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-
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articular rheumatism, dystrophinopathy, Glycogenolysis, polymyositis,
pyomyositis.
- Central pain or 'thalamic pain' as defined by pain caused by lesion or
dysfunction of the nervous system including but not limited to central post-
stroke
pain, multiple sclerosis, spinal cord injury, Parkinson's disease and
epilepsy.
- Heart and vascular pain including but not limited to angina, myocardical
infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma,
scleredoma, skeletal muscle ischemia.
- Visceral pain, and gastrointestinal disorders. The viscera encompasses
the organs of the abdominal cavity. These organs include the sex organs,
spleen
and part of the digestive system. Pain associated with the viscera can be
divided
into digestive visceral pain and non-digestive visceral pain. Commonly
encountered
gastrointestinal (GI) disorders include the functional bowel disorders (FBD)
and the
inflammatory bowel diseases (IBD). These GI disorders include a wide range of
disease states that are currently only moderately controlled, including - for
FBD,
gastro-esophageal reflux, dyspepsia, the irritable bowel syndrome (IBS) and
functional abdominal pain syndrome (FAPS), and - for IBD, Crohn's disease,
ileitis,
and ulcerative colitis, which all regularly produce visceral pain. Other types
of
visceral pain include the pain associated with dysmenorrhea, pelvic pain,
cystitis and
pancreatitis.
- Head pain including but not limited to migraine, migraine with aura,
migraine without aura cluster headache, tension-type headache.
- Orofacial pain including but not limited to dental pain,
temporomandibular myofascial pain.
The present invention provides a pharmaceutical composition for the
treatment of disease conditions caused by overactivation of NMDA NR2B
receptor,
in a mammalian subject, which comprises administering to said subject a
therapeutically effective amount of a compound of formula (I).
Further, the present invention also provides a composition which comprises
a therapeutically effective amount of the cycloalkylene amide compound of
formula
(I) or its pharmaceutically acceptable salt together with a pharmaceutically
acceptable carrier. Among them, the composition is preferably for the
treatment of
disease defined above.
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Also, the present invention provides for the use of a compound of formula
(n, or a pharmaceutically acceptable ester of such compound, or a
pharmaceutically
acceptable salt thereof, as a medicament.
Also, the present invention provides a method for the treatment of disease
conditions defined above, which comprises administering to said subject a
therapeutically effective amount of a compound of formula (I).
Further, the present invention provides a method for the treatment of
disease conditions defined above in a mammal, preferably human, which
comprises
administering to said subject a therapeutically effective amount of a compound
of
formula (n.
Yet further, the present invention provides the use of a therapeutically
effective amount of a compound of formula (n in the manufacture of a
medicament
for the treatment of the disease conditions defined above.
Detailed Description of the Invention
As used herein, the term "halogen" means fluoro, chloro, bromo and iodo,
preferably fluoro or chloro.
As used herein, the term "alkyl" means straight or branched chain saturated
radicals, including, but not limited to methyl, ethyl, ~-propyl, isopropyl, n-
butyl, iso-
butyl, secondary-butyl, tertiary-butyl.
As used herein, the term "alkoxy" means alkyl-O-, including, but not limited
to methoxy, ethoxy, n-propoxy, isopropoxy, ra-butoxy, iso-butoxy, secoyzdary-
butoxy,
tertiary-butoxy.
As used herein, the term "alkoxyalkyl" means alkyl-O-alkyl, including, but
not limited to methoxymethyl, methoxyethyl, methoxypropyl, methoxbutyl,
ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxbutyl, n-propoxymethyl, n-
propoxyethyl, fi-propoxypropyl, n-propoxybutyl, isopropoxymethyl,
isopropoxyethyl,
isopropoxypropyl, isopropoxybutyl, n-butoxymethyl, n-butoxyethyl, n-
butoxypropyl,
iso-butoxymethyl, iso-butoxyethyl, iso-butoxypropyl, iso-butoxybutyl,
secondary-
butoxymethyl, secoyidary-butoxyethyl, secondary-butoxypropyl, secondary-
butoxybutyl, tertiary-butoxymethyl, tertiary-butoxyethyl, tertiary-
butoxypropyl or
tertiary-butoxybutyl.
As used herein, the term "aryl" means a monocyclic or bicyclic aromatic
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carbocyclic ring of 6 to 10 carbon atoms, including, but not limited to,
phenyl or
naphtyl, preferably phenyl.
The term "heteroaryl" means a 5- to 10-membered monocyclic or bicyclic
aromatic heterocyclic ring which consists of from 1 to 4 heteroatoms
independently
selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen
atoms including, but not limited to, pyrazolyl, furyl, thienyl, oxazolyl,
tetrazolyl,
thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl,
thiophenyl,
pyrazinyl, pyridazinyl, isooxazolyl, isothiazolyl, triazolyl, furazanyl,
quinolyl,
isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromanyl or
isochromanyl
group, and the like.
The term "ordinary protecting group" means a protecting group, which can
be cleaved by a chemical method such as hydrogenolysis, hydrolysis,
electrolysis or
photolysis.
The term "esters " means a protecting group which can be cleaved in vivo by
a biological method such as hydrolysis and forms a free acid or salt thereof.
Whether
a compound is such a derivative or not can be determined by administering it
by
intravenous injection to an experimental animal, such as a rat or mouse, and
then
studying the body fluids of the animal to determine whether or not the
compound or
a pharmaceutically acceptable salt thereof can be detected.
Preferred examples of groups for an ester of a hydroxy group include: lower
aliphatic alkanoyl groups, for example: alkanoyl groups, such as the formyl,
acetyl,
propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl,
octanoyl,
nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-
dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl,
pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl,
13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl,
octadecanoyl,
1-methylheptadecanoyl, nonadecanoyl, icosanoyl and henicosanoyl groups;
halogenated alkylcarbonyl groups, such as the chloroacetyl, dichloroacetyl,
trichloroacetyl, and trifluoroacetyl groups; alkoxyalkylcarbonyl groups, such
as the
methoxyacetyl group; and unsaturated alkylcarbonyl groups, such as the
acryloyl,
propioloyl, methacryloyl, crotonoyl, isocrotonoyl and (E)-2-methyl- 2-butenoyl
groups; more preferably, the lower aliphatic alkanoyl groups having from 1 to
6
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carbon atoms; aromatic alkanoyl groups, for example: arylcarbonyl groups, such
as
the benzoyl, a -naphthoyl and ~3 -naphthoyl groups; halogenated arylcarbonyl
groups, such as the 2-bromobenzoyl and 4-chlorobenzoyol groups; lower
alkylated
arylcarbonyl groups, such as the 2, 4,6-trimethylbenzoyl and 4-toluoyl groups;
lower
5 alkoxylated arylcarbonyl groups, such as the 4-anisoyl group; nitrated
arylcarbonyl
groups, such as the 4-nitrobenzoyl and 2-nitrobenzoyl groups; lower
alkoxycarbonylated arylcarbonyl groups, such as the 2-(methoxycarbonyl)benzoyl
group; and arylated arylcarbonyl groups, such as the 4-phenylbenzoyl group;
alkoxycarbonyl groups, for example: lower alkoxycarbonyl groups, such as the
10 methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, sec-
butoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl groups; and halogen- or
tri(lower alkyl)silyl-substituted lower alkoxycarbonyl groups, such as the
2,2,2-
trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl groups;
tetrahydropyranyl or tetrahydrothiopyranyl groups, such as: tetrahydropyran- 2-
yl, 3
bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-
2
yl, and 4-methoxytetrahydrothiopyran-4-yl groups; tetrahydrofuranyl or
tetrahydrothiofuranyl groups, such as: tetrahydrofuran-2-yl and
tetrahydrothiofuran
2-yl groups; silyl groups, for example: tri(lower alkyl)silyl groups, such as
the
trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,
methyldiisopropylsilyl, methyldi-t-butylsilyl and triisopropylsilyl groups;
and
tri(lower alkyl)silyl groups substituted by 1 or 2 aryl groups, such as the
diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and
phenyldiisopropylsilyl groups; alkoxymethyl groups, for example: lower
alkoxymethyl groups, such as the methoxymethyl, 1,1-dimethyl-1-methoxymethyl,
ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl
groups; lower alkoxylated lower alkoxymethyl groups, such as the 2-
methoxyethoxymethyl group; and halo(lower alkoxy)methyl groups, such as the
2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl groups; substituted
ethyl
groups, for example: lower alkoxylated ethyl groups, such as the 1-ethoxyethyl
and
1-(isopropoxy)ethyl groups; and halogenated ethyl groups, such as the 2,2,2-
trichloroethyl group; aralkyl groups, for example: lower alkyl groups
substituted by
from 1 to 3 aryl groups, such as the benzyl, a -naphthylmethyl, ~3 -
naphthylmethyl,
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diphenylmethyl, triphenylmethyl, a - naphthyldiphenylmethyl and 9-
anthrylmethyl
groups; and lower alkyl groups substituted by from 1 to 3 substituted aryl
groups,
where one or more of the aryl groups is substituted by one or more lower
alkyl,
lower alkoxy, nitro, halogen or cyano substituents, such as the 4-
methylbenzyl,
2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-
methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-
bromobenzyl and 4-cyanobenzyl groups; alkenyloxycarbonyl groups: such as the
vinyloxycarbonyl and aryloxycarbonyl groups; and aralkyloxycarbonyl groups in
which the aryl ring may be substituted by 1 or 2 lower alkoxy or nitro groups:
such
as the benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-
dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-
nitrobenzyloxycarbonyl groups.
The term "treating", as used herein, refers to reversing, alleviating,
inhibiting the progress of, or preventing the disorder or condition to which
such term
applies, or one or more symptoms of such disorder or condition. The term
"treatment" as used herein refers to the act of treating, as "treating" is
defined
immediately above.
A preferred compound of formula (>7 of this invention is that wherein R1 and
R2 independently represents a hydrogen atom, a fluorine atom, a chlorine atom,
or
an alkyl group having from 1 to 4 carbon atoms. Most preferably Rl and R2
independently represent a hydrogen atom, a fluorine atom or an alkyl group
having
from 1 to 3 carbon atoms.
A preferred compound of formula (n of this invention is that wherein R3
represents an aryl group having from 6 to 7 ring carbon atoms or a heteroaryl
group
having from 5 to 10 ring atoms which consists of from 1 to 2 heteroatoms
independently selected from the group consisting of sulfur atoms, oxygen atoms
and
nitrogen atoms. More preferably, R3 represents a phenyl group, a thiazolyl
group,
an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a pyrrolyl
group, a
pyridyl group, a pyrimidine group, a quinolyl group, an isoquinolyl group, a
tetrahydroquinolyl group, a tetrahydroisoquinolyl group, a chromanyl group or
an
isochromanyl group. Most preferably, R3 represents a phenyl group, a thiazolyl
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12
group, a pyridyl group, or an isochromanyl group. R3 is preferably
unsubstituted or
substituted by one or two oc groups, preferably in the meta and/or para
position
relative to the point of attachment to the piperidyl ring. When R3 is phenyl,
it is
preferably substituted by one oc group, preferably halogen atoms, alkoxy
groups
having from 1 to 6 carbon atoms or alkoxyalkyl groups having from 1 to 6
carbon
atoms. When R3 is monocyclic heteroaryl, it is preferably substituted by one
or
two a groups, most preferably one, preferably halogen atoms, alkoxy groups
having
from 1 to 6 carbon atoms or alkoxyalkyl groups having from 1 to 6 carbon
atoms.
When R3 is 3-pyridyl, it is preferably substituted by 6-alkoxy groups having
from 1
to 6 carbon atoms.
A preferred individual compound of this invention is selected from
1-[2-(3-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]-4-(6-methoxypyridin-3-yl)-
piperidin-4-of methanesulfonate;
4-(3,4-Dihydro-1H isochromen-7-yl)-1-[2-(3-fluoro-4-hydroxyphenyl)-2-
hydroxyethyl]piperidin-4-of methanesulfonate;
1-[2-(3-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]-4-(3-fluorophenyl)piperidin-4-
of
methanesulfonate;
4-(3,4-Dihydro-1H-isochromen-7-yl)-1-[2-hydroxy-2-(4-hydroxy-3-
methylphenyl)ethyl]piperidin-4-ol;
4-(3-Fluorophenyl)-1-[2-hydroxy-2-(4-hydroxy-3-methylphenyl)ethyl]piperidin-4-
o1;
1-[2-Hydroxy-2-(4-hydroxy-3-methylphenyl)ethyl]-4-(6-methoxypyridin-3-yl)-
piperidin-4-ol;
1-[2-(2-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]-4-(3-fluorophenyl)piperidin-4-
ol;
4-(3,4-Dihydro-1H-isochromen-7-yl)-1-[2-(2-fluoro-4-hydroxyphenyl)-2-
hydroxyethyl]piperidin-4-ol;
1-[2-(2-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]-4-(6-methoxypyridin-3-
yl)piperidin-4-ol;
4-(3-Fluorophenyl)-1-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]piperidin-4-ol;
1-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(6-methoxypyridin-3-yl)piperidin-4-
ol;
1-[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]-4-[4-(methoxymethyl)phenyl]piperidin-4-
ol;
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13
1-[2-Hydroxy-2-(4-hydroxy-3-methylphenyl)ethyl]-4-[4-(methoxymethyl)phenyl]
piperidin-4-ol;
1-[2-Hydroxy-2-(4-hydroxy-3-methylphenyl)ethyl]-4-(5-methyl-1,3-thiazol-2-
yl)piperidin-4-ol;
1-[2-Hydroxy-2-(4-hydroxy-3-methylphenyl)ethyl]-4-(3-methoxyphenyl)-piperidin-
4-0l hydrochloride;
4-(6-Ethoxypyridin-3-yl)-1-[2-hydroxy-2-(4-hydroxy-3-methylphenyl)ethyl]-
piperidin-4-ol;
1-[2-(2-Fluoro-4-hydroxy-5-methylphenyl)-2- hydroxyethyl]-4-(6-methoxypyridin-3-
yl)piperidin-4-ol;
4-(6-Fluoro-5-methoxypyridin-2-yl)-1-[2-hydroxy-2-(4-hydroxy-3-
methylphenyl)ethyl]piperidin-4-ol;
1-[2-(3-chloro-4-hydroxyphenyl)-2-hydroxyethyl]-4-(6-methoxypyridin-3-
yl)piperidin-4-of hydrochloride;
1-[2-(3-chloro-4-hydroxyphenyl)-2-hydroxyethyl]-4-[4-
(methoxymethyl)phenyl]piperidin-4-ol;
1-[2-(2,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl]-4-(3-
fluorophenyl)piperidin-4-
ol; and
1-[2-(2,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl]-4-(6-methoxypyridin-3-
yl)piperidin-4-ol; or a pharmaceutically acceptable salt thereof.
A further preferred individual compound of this invention is selected from
1-[2-(3-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]-4-(3-fluorophenyl)piperidin-4-
of
methanesulfonate;
4-(3,4-Dihydro-1H-isochromen-7-yl)-1-[2-hydroxy-2-(4-hydroxy-3-
methylphenyl)ethyl]piperidin-4-ol;
4-(3-Fluorophenyl)-1-[2-hydroxy-2-(4-hydroxy-3-methylphenyl)ethyl]piperidin-4-
ol;
1-[2-Hydroxy-2-(4-hydroxy-3-methylphenyl)ethyl]-4-(6-methoxypyridin-3-yl)-
piperidin-4-ol;
1-[2-(2-Fluoro-4-hydroxyphenyl)-2-hydroxyethyl]-4-(3-fluorophenyl)piperidin-4-
ol;
4-(3,4-Dihydro-1H isochromen-7-yl)-1-[2-(2-fluoro-4-hydroxyphenyl)-2-
hydroxyethyl]piperidin-4-ol;
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14
4-(3-Fluorophenyl)-1-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]piperidin-4-ol;
1-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-4-(6-methoxypyridin-3-yl)piperidin-4-
ol;
1-[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]-4-[4-(methoxymethyl)phenyl]piperidin-4-
ol;
1-[2-Hydroxy-2-(4-hydroxy-3-methylphenyl)ethyl]-4-(3-methoxyphenyl)-piperidin-
4-0l hydrochloride;
4-(6-Ethoxypyridin-3-yl)-1-[2-hydroxy-2-(4-hydroxy-3-methylphenyl)ethyl]-
piperidin-4-ol;
1-[2-(2-Fluoro-4-hydroxy-5-methylphenyl)-2-hydroxyethyl]-4-(6-methoxypyridin-3-
yl)piperidin-4-ol; and
4-(6-Fluoro-5-methoxypyridin-2-yl)-1-[2-hydroxy-2-(4-hydroxy-3-
methylphenyl)ethyl]piperidin-4-ol;
or a pharmaceutically acceptable salt thereof.
General Synthesis
The compounds of the present invention may be prepared by a variety of
processes well known for the preparation of compounds of this type, for
example as
shown in the following reaction Schemes. Unless otherwise indicated Rl, RZ and
R3 in the reaction Schemes and discussion that follow are defined as above.
The
term "protecting group", as used hereinafter, means a hydroxy or amino
protecting
group which is selected from typical hydroxy or amino protecting groups
described
in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John
Wiley
& Sons, 1991);
The following reaction Schemes illustrate the preparation of compounds of
formula (n.
Scheme 1:
This illustrates the preparation of compounds of formula (n.
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R3 -Y
(1-1)
Step 1 A R1
s~_L I
O R OH PGz'p~Rz (1-6)
PGi N~ (1 2) PG , ~R3 deprotection
(1-3) Step 1 B 1 (1-4) Step 1 C H'N~ Step 1 D
(1-5)
OH OH
1 _ 3 1 3
Ri O N~ R reduction R OH ~-R 1 OH 3
_ I ; N deprotection R OH N~ R
PGz. , J_
O \Rz (1 _7) Step 1 E PGz'O ~Rz (1-8) Step 1 F HO I '~ z (i)
R
In the above formula, X represents a leaving group. Example of suitable
leaving groups include: halogen atoms, such as chlorine, bromine and iodine;
sulfonic esters such as Tf0 (triflates), Ms0 (mesylates), Ts0 (tosylates); and
the like.
5 Y represents a hydrogen atom, a halogen atom such as, fluorine, chlorine,
bromine
or iodine; .L represents metal such as lithium, or MgY. PG1 and PG~
independently represents a protecting group. The term "protecting group", as
used
herein, means a hydroxy or amino protecting group which is selected from
typical
hydroxy or amino protecting groups described in Protective Groups in Organic
10 Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1991). Typical
hydroxy or amino protecting groups include benzyl, C2H50(C=O)-, CH3(C=O)-, t-
butyldimethylsilyl (TBS), t-butyldiphenylsilyl, triisopropylsilyl (TIPS),
methoxymethyl (MOM), benzyloxycarbonyl represented as Z and t-buthoxycarbonyl
represented as t-Boc or Boc.
15 Step
In this Step, the organometallic compound of formula (1-2) can be prepared
by reaction of a halide compound of formula (1-1). This reaction may be
carried
out in the presence of an organometallic reagent or a metal. Examples of
suitable
organometallic reagents include; alkyllithiums such as n-butyllithium, sec-
butyllithium and tert-butyllithium; aryllithiums such as phenyllithium and
lithium
naphtilide. Examples of suitable metal include magnesium. . Preferred reaction
inert solvents include, for example, hydrocarbons, such as hexane; ethers,
such as
diethyl ether, diisopropyl ether, dimethoxyethane (DME) tetrahydrofuran (THF)
and
dioxane; or mixtures thereof. Reaction temperatures are generally in the range
of -
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16
100 to 50 °C, preferably in the range of from -100 °C. to room
temperature.
Reaction times are, in general, from 1 minute to a day, preferably from 1 hour
to 10
hours.
Step 1B
In this Step, an alcohol compound of formula (1-4) can be prepared by the
nucleophilic addition of a ketone compound of formula (1-1) with the
organometallic compound of formula (1-2). The reaction may be carried out in
the
presence of a solvent. Examples of suitable solvents include for example,
hydrocarbons, such as hexane; ethers, such as diethyl ether, diisopropyl
ether,
dimethoxyethane (DME) tetrahydrofuran (THF) and dioxane; or mixtures thereof.
Reaction temperatures are generally in the range of -100 to 50 °C,
preferably in the
range of from -100 °C. to room temperature. Reaction times are, in
general, from 1
minute to a day, preferably from 1 hour to 10 hours.
Ste~lC
In this Step, the desired compound of formula (1-5) may be prepared by the
deprotection of the compound of formula 1-4, prepared as described in Step 1B,
according to known procedures such as those described in Protective Groups in
Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1991).
In the case of Boc protection, the removal of the protecting groups may be
carried out under known conditions in the presence or the absence of catalytic
amount of an acid in a reaction inert solvent. Example of suitable aqueous or
non-
aqueous organic reaction inert solvents include: ethyl acetate; alcohols, such
as
methanol and ethanol; ethers, such as tetrahydrofuran and dioxane; acetone;
dimethylformamide; halogenated hydrocarbons, such as dichloromethane,
dichloroethane or chloroform; and acetic acid or mixtures thereof. The
reaction
may be carried out at a temperature in the range from of 0 °C to 200
°C, preferably
in the range of 20°C to 120°C. Reaction times are, in general,
from 1 minute to 48
hours, preferably 5 minutes to 24 hours. Example of suitable catalysts
include:
hydrogen halide, such as hydrogen chloride and hydrogen bromide; sulfonic
acids,
such as p-toluenesulfonic acid and, benzenesulfonic acid; ammonium salts, such
as
pyridium p-toluenesulfonate and ammonium chloride; and carboxylic acid, such
as
acetic acid and trifluoroacetic acid.
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17
In the case of Bn or Z protection, the removal of the protecting groups may
be carried out under, for example, known hydrogenolysis conditions in the
presence
of a metal catalyst under hydrogen atmosphere or in the presence of hydrogen
sources such as formic acid or ammonium formate in a reaction inert solvent.
If
desired, the reaction is carried out under acidic conditions, for example, in
the
presence of hydrochloric acid or acetic acid. A preferred metal catalyst is
selected
from, for example, palladium-carbon, palladiumhydroxide-carbon, platinumoxide,
platinum-carbon, ruthenium-carbon, rhodium-aluminumoxide,
tris[triphenyphosphine] rhodiumchlrodie. Example of suitable reaction inert
aqueous or non-aqueous organic solvents include: alcohols, such as methanol,
ethanol; ethers, such as tetrahydrofuran or dioxane; acetone;
dimethylformamide;
halogenated hydrocarbons, such as dichloromethane, dichloroethane or
chloroform;
and acetic acid or mixtures thereof. The reaction may be carried out at a
temperature in the range from of 20 °C to 100 °C, preferably in
the range of 20°C to
60°C. Reaction times are, in general, from 10 minutes to 48 hours,
preferably 30
minutes to 24 hours. This reaction may be carried out under hydrogen
atmosphere
at a pressure ranging from 1 to 100 atom, preferably from 1 to 10 atom.
In the case of ethoxycarbonyl protection, the removal of the protecting
groups may be carried out under known conditions. In a typical procedure, this
reaction can be carried out by treatment with sodium hydroxide, lithium
hydroxide,
trimethylsilyl iodide or alkylthiolithium such as n-propylthiolithium in a
reaction
inert solvent. Suitable solvents include, for example, alcohols such as
methanol,
ethanol, propanol, butanol, 2-methoxyethanol, and ethlene gylcol; ethers such
as
tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), and 1,4-dioxane; halogenated
hydrocarbons such as chloroform, dichloroethane, and 1,2-dichloroethane;
amides
such as N,N-dimethylformamide (DMF) and hexamethylphospholictriamide; and
sulfoxides such as dimethyl sulfoxide (DMSO). This reaction may be carried out
at a temperature in the range from -10 to 200°C, usually from
0°C to 120°C for 30
minutes to 24 hours, usually 60 minutes to 10 hour.
Step 1D
In this Step, the desired beta-carbonyl piperidne compound of formula 1-7
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18
may be prepared by the coupling of a halide compound of formula 1-6 with the
piperidine compound of formula 1-5 in an inert solvent, e.g. aliphatic
hydrocarbons,
such as hexane, heptane and petroleum ether; aromatic hydrocarbons, such as
benzene, toluene, xylene and nitrobenzene; halogenated hydrocarbons, such as
methylene chloride, chloroform, carbon tetrachloride and dichloroethane;
ethers,
such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane;
alcohols, such
as methanol, ethanol, propanol, isopropanol and butanol; and dimethylformamide
(DMF), dimethylsulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone(DMn or
acetonitrile. This reaction may be carried out in the presence of a base, e.g.
an
alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride,
such as
sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide,
potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium
carbonate,
sodium hydride or potassium hydride, or an amine such as triethylamine,
tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine. This
reaction may be carried out in the presence of a suitable additive, e.g.
tetrakis(triphenylphosphine)-palladium, bis(triphenylphosphine)palladium(In
chloride, copper(0), copper( acetate, copper( bromide, copper( chloride,
copper(n iodide, copper(n oxide, copper( trifluoromethanesulfonate, copper(1~
acetate, copper(I~ bromide, copper(I~ chloride, copper(II) iodide, copper(1~
oxide,
1,10-phenanthroline, dibenzanthracene(DBA) or copper(I~
trifluoromethanesulfonate. The reaction may be carried out at a temperature in
the
range from of 0 °C to 100 °C, preferably in the range of
20°C to 100°C. Reaction
times are, in general, from 5 minutes to 48 hours, preferably 30 minutes to 24
hours.
Step 1E
In this Step, an alcohol compound of formula (1-8) can be prepared by the
reduction of the ketone compound of formula (1-7) with a reducing agent, e.g.
NaBH4, LiAlH4, LiBH4, or ZnBH4 in an inert solvent, e.g. methanol, ethanol,
diglyme, or mixtures thereof. The reaction may be carried out at a temperature
in
the range from of 0 °C to 100 °C, preferably in the range of
20°C to 80°C. Reaction
times are, in general, from 5 minutes to 48 hours, preferably 30 minutes to 24
hours.
Step 1F
In this Step, the desired compound of formula (n may be prepared by the
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19
deprotection of the compound of formula (1-8).
This reaction is essentially the same as and may be carried out in the same
manner as and using the same reagents and reaction conditions as Step 1C in
Scheme 1.
In the case of silyl derivatives protection, the removal of the protecting
groups may be carried out under known conditions. In a typical procedure, this
reaction can be carried out by treatment with tetrabutylammonium fluoride in
tetrahydrofuran. This reaction can be also carried out under the acidic
conditions
in a reaction inert solvent. Example of suitable aqueous or non-aqueous
organic
reaction inert solvents include: alcohols, such as methanol and ethanol;
ethers, such
as tetrahydrofuran and dioxane; acetone; dimethylformamide; and acetic acid or
mixtures thereof. The reaction may be carried out at a temperature in the
range
from of -10 °C to 200 °C, preferably in the range of 0°C
to 120°C. Reaction times
are, in general, from 1 minute to 48 hours, preferably 5 minutes to 24 hours.
Example of suitable acids include: hydrogen halide, such as hydrogen chloride
and
hydrogen bromide; sulfonic acids, such as p-toluenesulfonic acid and,
benzenesulfonic acid; ammonium salts, such as pyridium p-toluenesulfonate and
ammonium chloride; and carboxylic acid, such as acetic acid and
trifluoroacetic acid.
Scheme 2
Ri O OH 3 R~ OH 3 R1 O ~R3
~~~X + , ~R _ \\\ O N~R Pro ~ ~J~-N
HO~~J H ~ ~ Step 2B ' PG~. I ~\
R2 ~2-1) (1-5) Step 2A HO -\R2 X2_2) O R2 ~1
OH ~ ~ H 3
reduction RIi OH ~R3 R OH R
deprotection ~ N
N I
Step 2C PG2,0~~ Step 2D HO~ i
R2 ~~_g) R2 ~ )
Ste~2A
In this Step, the desired beta-carbonyl piperidne compound of formula 2-2
may be prepared by the coupling of a halide compound of formula 2-1 with the
piperidine compound of formula 1-5. This reaction is essentially the same as
and
may be carried out in the same manner as and using the same reagents and
reaction
conditions as Step 1D in Scheme 1.
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Step 2B
In this Step, the protected compound of formula (1-7) may be prepared
from the compound of formula (2-2) by converting the OH group into a protected
O
group. The step may be carried out by using, for example, the compound of
5 formula (2-2), appropriate triethyl orthoformate, silyl halides, aralkyl
halide, acid
halides, acid anhydride and acids, such as benzyl, t-butyldimethylsilyl (TBS)
chloride, t-butyldiphenylsilylchloride, Z-chloride and t-BocCl or Boc20, using
the
methods described in Protective Groups in Organic Synthesis edited by T. W.
Greene et al. (John Wiley & Sons, 1991). Of these reagents, we prefer triethyl
10 orthoformate. The reaction may be carried out in the presence or absence of
a
solvent, e.g. aromatic hydrocarbons, such as benzene, toluene and xylene;
halogenated hydrocarbons, such as methylene chloride, chloroform, carbon
tetrachloride and dichloroethane; and ethers, such as diethyl ether,
diisopropyl ether,
tetrahydrofuran and dioxane; and DMF and DMSO. This reaction may be carried
15 out in the presence or absence of a catalyst, e.g. para-toluenesulfonic
acid,
camphorsulfonic acid, and acetic acid.
Step 2C and 2D
In these Steps, the desired compound of formula (~ may be prepared by the
reduction of the ketone compound of formula (1-7) followed by the deprotection
of
20 the compound of formula (1-8).
These reactions are essentially the same as and may be carried out in the
same manner as and using the same reagents and reaction conditions as Step 1E
and
1F in Scheme 1.
Scheme 3
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21
R1
~~Y
L'O I~~..~R2 Step 3A
X3_1) ~ ~Y1
L
OH L'0~~2 1 OH 1 OHg
R 3 Protection R ~ O ~R
MeO. ~N~R3 ~3 2) R I~N~ R
Me Step 3B HO~~JJ 2-2 Step 3C PG2.~~
X3_3) R2 ~ ) R2 X1_7)
OH OH
1 3 1 3
reduction IRI off ~R deprotection IR % off N~R
Step 3D PG2,0~~JYv ~1_$) Step 3E HO~ Ji
R2 R2 C)
In the above formula, Y represents a halogen atom such as, fluorine, chlorine,
bromine or iodine; .L represents metal such as lithium, or MgY.
Step 3A
In this Step, the organometallic compound of formula (3-2,) can be prepared
by reaction of a halide compound of formula (3-1). This reaction may be
carried
out in the presence of an organometallic reagent or a metal. Examples of
suitable
organometallic reagents include; alkyllithiums such as n-butyllithium, sec-
butyllithium and tert-butyllithium; aryllithiums such as phenyllithium and
lithium
naphtilide. Examples of suitable metal include magnesium. . Preferred reaction
inert solvents include, for example, hydrocarbons, such as hexane; ethers,
such as
diethyl ether, diisopropyl ether, dimethoxyethane (DME) tetrahydrofuran (THF)
and
dioxane; or mixtures thereof. Reaction temperatures are generally in the range
of -
100 to 50 °C, preferably in the range of from -100 °C. to room
temperature.
Reaction times are, in general, from 1 minute to a day, preferably from 1 hour
to 10
hours.
Step 3B
In this Step, the desired beta-carbonyl piperidine compound of formula 2-2
may be prepared by the coupling of the amide compound of formula 3-2 with a
Weinreb amide compound of formula 3-3. The reaction may be carried out in the
presence of a solvent. Examples of suitable solvents include for example,
hydrocarbons, such as hexane; ethers, such as diethyl ether, diisopropyl
ether,
dimethoxyethane (DME) tetrahydrofuran (THF) and dioxane; or mixtures thereof.
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22
Reaction temperatures are generally in the range of -100 to 50 °C,
preferably in the
range of from -100 °C. to room temperature. Reaction times are, in
general, from 1
minute to a day, preferably from 1 hour to 10 hours.
Step 3C
In this Step, the protected compound of formula (1-7) may be prepared
from the compound of formula (2-2) by converting the OH group into a protected
O
group.
These reactions are essentially the same as and may be carried out in the
same manner as and using the same reagents and reaction conditions as Step 1E
and
2B in Scheme 2.
Step 3D and 3E
In these Steps, the desired compound of formula (n may be prepared by the
reduction of the ketone compound of formula (1-7) followed by the deprotection
of
the compound of formula (1-8).
These reactions are essentially the same as and may be carried out in the
same manner as and using the same reagents and reaction conditions as Step 1E
and
1F in Scheme 1.
Scheme 4
OR4
ORS
Ri O HN 1 OR4 ~ OR4
(4'1 ) R O N~ORS reduction R OH N~ORS
PGz.O ~ ~ ~ ~ I Jw
Rz (1-6) Step 4A PGz.O I .~ Step 4B PGz,O I
Rz (4_2) Rz (4_3)
R3 -Y
(1-1)
Step 4D
R~ -L
deprotection R1 OH N~O (1-2) Ri OH N~R3 deprotection R1 OH R3
~ ,~ ~ I~ N
Step 4C Gz, I ~ Step 4E PGz, I ~ Step 4F HO ~ (i)
O Rz (4 4) O R2 (1'8) Rz
In the above formula, R4 and R5 represents an alkyl group or R4 and R5
may be joined together to form an ethylene or a propylene group; said ethylene
or
propylene group are optionally substituted by hydroxy groups.
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23
Step 4A
In this Step, a desired beta-carbonyl piperidne compound of formula 4-2
may be prepared by the coupling of a halide compound of formula 1-6 with an
ketal
piperidine compound of formula 4-1. This reaction is essentially the same as
and
may be carried out in the same manner as and using the same reagents and
reaction
conditions as Step 1D in Scheme 1.
Step 4B
In this Step, an alcohol compound of formula (4-3) can be prepared by the
reduction of the ketone compound of formula (4-2) with a reducing agent. This
reaction is essentially the same as and may be carried out in the same manner
as and
using the same reagents and reaction conditions as Step 1E in Scheme 1.
Step 4C
In this Step, a piperidone compound of formula (4-4) can be prepared by
the deprotection of the ketal compound of formula (4-3) in the presence or the
absence of a catalyst in a reaction-inert solvent.
The hydrolysis reaction may be carried out in an aqueous or non-aqueous
organic
solvent. Examples of suitable solvents include: alcohols, such as methanol or
ethanol; ethers, such as tetrahydrofuran or dioxane; acetone;
dimethylformamide;
halogenated hydrocarbons, such as dichloromethane, dichloroethane or
chloroform;
acids, such as acetic acid, hydrogen chloride, hydrogen bromide and sulfuric
acid.
Example of suitable catalysts include: hydrogen halides, such as hydrogen
chloride
and hydrogen bromide; sulfonic ' acids, such as p-toluenesulfonic acid and
benzenesulfonic acid; ammonium salts, such as pyridium p-toluenesulfonate and
ammonium chloride; and carboxylic acid, such as acetic acid and
trifluoroacetic acid.
This reaction can be carried out at temperature of 0 ~C to 200 ~C, preferably
from
about 20 ~C to 120 ~C for 5 minutes to 48 hours, preferably 30 minutes to 24
hours.
Step 4D
In this Step, the organometallic compound of formula (1-2) can be prepared
by reaction of a halide compound of formula (1-1) in the same manner as and
using
the same reagents and reaction conditions as Step 1A in Scheme 1.
Step 4E
In this Step, the alcohol compound of formula (1-8) can be prepared by the
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24
nucleophilic addition of the ketone compound of formula (4-4) with the
organometallic compound of formula (1-2). This reaction is essentially the
same as
and may be carried out in the same manner as and using the same reagents and
reaction conditions as Step 1B in Scheme 1.
Step 4F
In this Step, the desired compound of formula (~ may be prepared by the
deprotection of the compound of formula (1-8).
This reaction is essentially the same as and may be carried out in the same
manner as and using the same reagents and reaction conditions as Step 1C or 1F
in
Scheme 1.
The starting materials in the aforementioned general syntheses may be
commercially available or obtained by conventional methods known to those
skilled
in the art.
In the above Schemes from 1 to 4, examples of suitable solvents include a
mixture of any two or more of those solvents described in each Step.
The compounds of formula (n, and the intermediates above-mentioned
preparation methods can be isolated and purified by conventional procedures,
such
as recrystallization or chromatographic purification.
The optically active compounds of this invention can be prepared by several
methods. For example, the optically active compounds of this invention may be
obtained by chromatographic separation, enzymatic resolution or fractional
crystallization from the final compounds.
Method for assessing biological activities:
NR2B binding Assay
The activity of the bicyclic amide compounds of the present invention, as
NR2B antagonists, is determined by their ability to inhibit the binding of
NR2B
subunit at its receptor sites employing radioactive ligands.
The NR2B antagonist activity of the bicyclic amide compounds is evaluated
by using the standard assay procedure described in, for example, J.
Pharmacol., 331,
pp117-126, 1997. This method essentially involves determining the
concentration
of the individual compound required to reduce the amount of radiolabelled NR2B
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ligands by 50% at their receptor sites, thereby affording characteristic ICSO
values for
each compound tested. More specifically, the assay is carried out as follows.
Membranes were prepared by homogenization of forebrain of male CD rats
weighing between 170 190 g by using glass-Teflon homogenizer in 0.32 M sucrose
5 at 4°C. The crude nuclear pellet was removed by centrifugation at
1000xg for 10
min, and the supernatant centrifuged at 17000xg for 25 min. The resulting
pellet
was resuspended in 5 mM Tris acetate pH 7.4 at 4°C for 10 min to lyse
cellular
particles and again centrifuged at 17000xg. The resulting pellet (P2 membrane)
was washed twice in Tris acetate, resuspended at 5.5 mg protein/ml and stored
at -
10 20°C until use. All the manipulation was done on ice, and stock
solution and
equipment were kept on ice at all time.
For the saturation assay, receptor saturation was determined by incubating
[3H]-CP-98,113 and 50 ~,g protein of P2 membrane for 60 minutes at room
temperature in a final 100 ~,1 of incubation buffer (50 mM Tris HCI, pH7.4).
Total
15 and non-specific bindings (in the presence of 10 ~,M of unlabeled CP-
98,113) were
determined in a range of [3H]-CP-98113 concentrations (0.625 nM to 60nM).
[3H]-CP-98,113 is as follows:
(wherein T is tritio (3H)).
For the competition assay, test compounds were incubated in duplicate with
20 5 nM [3H]-CP-98,113 and 50 ~g protein of P2 membrane for 60 minutes at room
temperature in a final 100 ~,1 of 50 mM Tris HCl buffer (pH7.4). Nonspecific
binding was determined by 10 ~,M of unlabeled CP-98,113 (25 ~,1). The
saturation
derived KD gained in saturation assay was used for all Ki calculations.
All incubations were terminated by rapid vacuum filtration over 0.2%
25 polyethyleneimine soaked Whatman GFB glass fibre filter paper using a
SKATRON cell harvester followed by three washes with ice-cold filtration
buffer (5
mM Tris HCI, pH 7.4.). Receptor-bound radioactivity was quantified by liquid
scintillation counting using Packard LS counter. Competition assays were
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WO 2005/035522 PCT/IB2004/003127
26
performed by counting Wallac GFB filters on Betaplate scintillation counter
(Wallac).
All compounds prepared in the working examples as described below were
tested by this method, and they showed Ki values from 2 nM to 20 nM with
respect
to inhibition of binding at the NR2B receptor.
Human NR2B cell functional assay
HEK293 cells stably expressing human NRlb/2B receptor were used for
cell functional assay. Cells were grown in 75-cm' culture flasks, using
Dulbecco's
modified Eagle's medium (DMEM, high glucose) supplemented with 10% fetal
bovine, 52 ~,g/ml Zeocin, 530 [ug/ml Geneticin, 100 units/ml penicillin and
100
p,ghnl streptomycin. Cells were maintained in a humidified atmosphere in 5%
C02
at 37°C, and 50-60% confluent cells were harvested by 0.05% trypsin
containing
0.53 mM EDTA. The day before the experiment, expression of NRlb/2B receptor
was induced by 5 ~M ponasteron A in DMEM (40 ml) in the presence of 400 ~M
ketamine to prevent excitotoxicity. The induction was performed for 19-24
hours,
using 50-60% confluent cells.
Cells were washed with 10 ml of Ca2+-free Krebs-Ringer Hepes buffer
(KRH) containing 400 ~tM ketamine, and the loading of 5 p,M fura-2
acetoxymethyl
ester was made for 2hrs at room temperature in the presence of 400 p,M
ketamine in
Ca2+-free KRH (10 ml). Subsequently, cells were collected in 50 ml tube by
pipetting manipulation and centrifuged at 850 rpm for 2 min. Supernatant was
removed, and cells were washed with 10 ml of Ca2+-free KRH buffer, followed by
centrifugation again. This manipulation was repeated 4 times to remove
ketamine,
glutamate and glycine. Cells were re-suspended in Ca2+-free KRH buffer, and 50
~,1
of cell suspension was added to each well of 96-well plates at a density of
100,000
cells/well, followed by adding test compounds dissolved in 50 ~,1 of Ca2+-free
KRH.
After pre-incubation for 30 min, agonists (final 100 p,M glutamic acid and 10
p.M
glycine) dissolved in 25 ~,1 of KRH containing 9 mM Caz+ (final 1.8 mM) were
added. Fura-2 fluorescence (excitation wavelengths: 340 nm and 380 nm;
emission wavelengths 510-520 nm) was monitored with a fluorescence imaging
system, FDSS6000. The 0 fluorescence ratio F340/F380 (i.e., the fluorescence
ratio immediately post-agonist - the basal fluorescence ratio; calculated as
AUC)
was used for evaluation of drug effects on agonists-induced changes in
intracellular
Ca2+. The basal fluorescence ratio was determined in the presence of 10 ~,M MK-
801.
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27
rat haloperidol-induced catalepsy assay:
Fasted male CD rats were used (7-8 weeks old). Test compound or
vehicle was given subcutaneously then haloperidol 0.5 mg/kg s.c.. Sixty
minutes
after haloperidol-injection, the duration of catalepsy was quantified by
placing the
animals forepaws on an elevated bar and determining the latency to remove both
forepaws from the bar. The cutoff latency was 60 seconds. Experimenter was
blind to treatments during testing.
Human dofetilide binding
Human HERG transfected HEK293S cells were prepared and grown in-house. The
collected cells were suspended in 50 mM Tris-HCl (pH 7.4 at 4°C) and
homogenized using a hand held Polytron PT 1200 disruptor set at full power for
20
sec on ice. The homogenates were centrifuged at 48,000 x g at 4 °C for
20 min. The
pellets were then resuspended, homogenized, and centrifuged once more in the
same
manner. The final pellets were resuspended in an appropriate volume of 50 mM
Tris-HCI, 10 mM KCl, 1 mM MgCl2 (pH 7.4 at 4°C), homogenized,
aliquoted and
stored at -80°C until use. An aliquot of membrane fractions was used
for protein
concentration determination using BCA protein assay kit (PIERCE) and ARVOsx
plate reader (Wallac).
Binding assays were conducted in a total volume of 200 ~1 in 96-well plates.
Twenty
~,1 of test compounds were incubated with 20 ~,l of [3H]-dofetilide (Amersham,
final
5 nM) and 160 ~l of membrane homogenate (25 ~,g protein) for 60 minutes at
room
temperature. Nonspecific binding was determined by 10 ~,M dofetilide at the
final
concentration. Incubation was terminated by rapid vacuum filtration over 0.5%
presoaked GFIB Betaplate filter using Skatron cell harvester with 50 mM Tris-
HCI,
10 mM KCI, 1 mM MgCl2, pH 7.4 at 4°C. The filters were dried, put into
sample
bags and filled with Betaplate Scint. Radioactivity bound to filter was
counted with
Wallac Betaplate counter.
All compounds prepared in the working examples as described below
showed a TI (TI is a value of { Dofetilide Binding Ki [~,M ]/ NR2B Binding Ki
[nM]x1000} value in the range of 500-3800, whereas a structurally similar
comparative compound A showed a TI value of 220.
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28
ERG assay
HEK 293 cells which stably express the HERD potassium channel were used
for electrophysiological study. The methodology for stable transfection of
this
channel in HEK cells can be found elsewhere (Z.Zhou et al., 1998, Biophysical
journal, 74, pp230-241). Before the day of experimentation, the cells were
harvested from culture flasks and plated onto glass coverslips in a standard
MEM
medium with 10% FCS. The plated cells were stored in an incubator at
37°C
maintained in an atmosphere of 95%02/5%CO2. Cells were studied between 15-
28hrs after harvest.
HERG currents were studied using standard patch clamp techniques in the
whole-cell mode. During the experiment the cells were superfused with a
standard
external solution of the following composition (mM); NaCI, 130; KCl, 4; CaCl2,
2;
MgCl2, 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH. Whole-cell recordings was
made using a patch clamp amplifier and patch pipettes which have a resistance
of 1-
3MOhm when filled with the standard internal solution of the following
composition (mM); KCI, 130; MgATP, 5; MgCl2, 1.0; HEPES, 10; EGTA 5, pH 7.2
with KOH. Only those cells with access resistances below 15MS2 and seal
resistances >1GS~ was accepted for further experimentation. Series resistance
compensation was applied up to a maximum of 80%. No leak subtraction was
done. However, acceptable access resistance depended on the size of the
recorded
currents and the level of series resistance compensation that can safely be
used.
Following the achievement of whole cell configuration and sufficient for cell
dialysis with pipette solution (>5min), a standard voltage protocol was
applied to the
cell to evoke membrane currents. The voltage protocol is as follows. The
membrane was depolarized from a holding potential of -80mV to +20mV for
1000ms. This was followed by a descending voltage ramp (rate 0.5mV msec 1)
back to the holding potential. The voltage protocol was applied to a cell
continuously throughout the experiment every 4 seconds (0.25Hz). The amplitude
of the peak current elicited around -40mV during the ramp was measured. Once
stable evoked current responses were obtained in the external solution,
vehicle
(0.5% DMSO in the standard external solution) was applied for 10-20 min by a
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29
peristalic pump. Provided there were minimal changes in the amplitude of the
evoked current response in the vehicle control condition, the test compound of
either
0.3, 1, 3, 10~,M was applied for a 10 min period. The 10 min period included
the
time which supplying solution was passing through the tube from solution
reservoir
to the recording chamber via the pump. Exposing time of cells to the compound
solution was more than 5min after the drug concentration in the chamber well
reached the attempting concentration. There reversibility. Finally, the cells
was
exposed to high dose of dofetilide (5~,M), a specific II~r blocker, to
evaluate the
insensitive endogenous current.
All experiments were performed at room temperature (23 ~ 1 °C).
Evoked
membrane currents were recorded on-line on a computer, filtered at 500-lKHz
(Bessel -3dB) and sampled at 1-2KHz using the patch clamp amplifier and a
specific
data analyzing software. Peak current amplitude, which occurred at around -
40mV,
was measured off line on the computer.
The arithmetic mean of the ten values of amplitude was calculated under
control
conditions and in the presence of drug. Percent decrease of IN in each
experiment
was obtained by the normalized current value using the following formula: IN =
(1- Io/Io )x100, where ID is the mean current value in the presence of drug
and Ic is
the mean current value under control conditions. Separate experiments were
performed for each drug concentration or time-matched control, and arithmetic
mean in each experiment is defined as the result of the study.
Mice PSL Method
Surgery of partial sciatic nerve ligation (PSL) was made according to Seltzer
et al.
(Pain 43, 1990, 205-218). Von Fray hair test was applied slowly to the plantar
surface of the hind operated paw until the hairs bent. Each hair was tested 10
times
in ascending order of force to different loci of the paw with one to two
second
intervals between each application. Once a withdrawal response was
established,
the paw was re-tested with the same hair. The lowest amount of force required
to
elicit a response was recorded as the paw-withdrawal threshold, measured in
grams.
Chronic Contriction Injury Model (CCI Model):
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Male Sprague-Dawley rats (270-300 g; B.W., Charles River, Tsukuba, Japan) were
used.
The chronic constriction injury (CCI) operation was performed according to the
method described by Bennett and Xie 1~. Briefly, animals were anesthetized
with
5 sodium pentobarbital (64.8 mg/kg, i.p.) and the left common sciatic nerve
was
exposed at the level of the middle of the thigh by blunt dissection through
biceps
femoris. Proximal to the sciatic's trifurcation was freed of adhering tissue
and 4
ligatures (4-0 silk) were tided loosely around it with about 1 mm space. Sham
operation was performed as same as CCI surgery except for sciatic nerve
ligation.
10 Two weeks after surgery, mechanical allodynia was evaluated by application
of von
Frey hairs (VFHs) to the plantar surface of the hind paw. The lowest amount of
force of VFH required to elicit a response was recorded as paw withdrawal
threshold
(PWT). VFH test was performed at 0.5, 1 and 2 hr post-dosing. Experimental
data were analyzed using Kruskal-Wallis test followed by Dunn's test for
multiple
15 comparisons or Mann-Whitney U-test for paired comparison.
1~ Bennett, G.J. and Xie, Y.K. Pai~a, 33:87-107,1988
Pharmaceutically acceptable salts of the compounds of formula (I) include
the acid addition and base salts (including disalts) thereof.
20 Suitable acid addition salts are formed from acids which form non-toxic
salts.
Examples include the acetate, aspartate, benzoate, besylate,
bicarbonate/carbonate,
bisulphate, camsylate, citrate, edisylate, esylate, fumarate, gluceptate,
gluconate,
glucuronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide,
hydroiodide/iodide, hydrogen phosphate, isethionate, D- and L-lactate, malate,
25 maleate, malonate, mesylate, methylsulphate, 2-napsylate, nicotinate,
nitrate, orotate,
palmoate, phosphate, saccharate, stearate, succinate sulphate, D- and L-
tartrate, and
tosylate salts. Suitable base salts are formed from bases which form non-toxic
salts.
Examples include the aluminium, arginine, benzathine, calcium, choline,
diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,
30 potassium, sodium, tromethamine and zinc salts.
For a review on suitable salts, see Stahl and Wermuth, Handbook of
Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim,
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31
Germany (2002).
A pharmaceutically acceptable salt of a compound of formula (~ may be readily
prepared by mixing together solutions of the compound of formula (~ and the
desired acid or base, as appropriate. The salt may precipitate from solution
and be
collected by filtration or may be recovered by evaporation of the solvent.
Pharmaceutically acceptable solvates in accordance with the invention include
hydrates and solvates wherein the solvent of crystallization may be
isotopically
substituted, e.g. D20, d6-acetone, d6-DMSO.
Also within the scope of the invention are clathrates, drug-host inclusion
complexes
wherein, in contrast to the aforementioned solvates, the drug and host are
present in
non-stoichiometric amounts. For a review of such complexes, see J Pharm Sci,
64
(8), 1269-1288 by Haleblian (August 1975).
Hereinafter all references to compounds of formula (n include references to
salts
thereof and to solvates and clathrates of compounds of formula (n and salts
thereof.
The invention includes all polymorphs of the compounds of formula (~ as
hereinbefore defined.
Also within the scope of the invention are so-called "prodrugs" of the
compounds of
formula (1). Thus certain derivatives of compounds of formula (I) which have
little
or no pharmacological activity themselves can, when metabolised upon
administration into or onto the body, give rise to compounds of formula (1]
having
the desired activity. Such derivatives are referred to as "prodrugs".
Prodrugs in accordance with the invention can, for example, be produced by
replacing appropriate functionalities present in the compounds of formula (n
with
certain moieties known to those skilled in the art as "pro-moieties" as
described, for
example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).
Finally, certain compounds of formula (n may themselves act as prodrugs of
other
compounds of formula (~.
Compounds of formula (n containing one or more asymmetric carbon atoms can
exist as two or more optical isomers. Where a compound of formula (n contains
an
alkenyl or alkenylene group, geometric cisltrans (or Z/E) isomers are
possible, and
where the compound contains, for example, a keto or oxime group, tautomeric
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32
isomerism ('tautomerism') may occur. It follows that a single compound may
exhibit more than one type of isomerism.
Included within the scope of the present invention are all optical isomers,
geometric
isomers and tautomeric forms of the compounds of formula (I), including
compounds exhibiting more than one type of isomerism, and mixtures of one or
more thereof.
Cisltrans isomers may be separated by conventional techniques well known to
those
skilled in the art, for example, fractional crystallization and
chromatography.
Conventional techniques for the preparation/isolation of individual
stereoisomers
include the conversion of a suitable optically pure precursor, resolution of
the
racemate (or the racemate of a salt or derivative) using, for example, chiral
HPLC,
or fractional crystallization of diastereoisomeric salts formed by reaction of
the
racemate with a suitable optically active acid or base, for example, tartaric
acid.
The present invention also includes all pharmaceutically acceptable isotopic
variations of a compound of formula (I). An isotopic variation is defined as
one in
which at least one atom is replaced by an atom having the same atomic number,
but
an atomic mass different from the atomic mass usually found in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention
include isotopes of hydrogen, such as 2H and 3H, carbon, such as 13C and 14C,
nitrogen, such as 15N, oxygen, such as 1'O and 180, phosphorus, such as 32P,
sulphur,
such as 355, fluorine, such as 18F, and chlorine, such as 36C1.
Substitution of the compounds of the invention with isotopes such as
deuterium, i.e.
2H, may afford certain therapeutic advantages resulting from greater metabolic
stability, for example, increased in vivo half life or reduced dosage
requirements,
and hence may be preferred in some circumstances.
Certain isotopic variations of the compounds of formula (I), for example,
those
incorporating a radioactive isotope, are useful in drug and/or substrate
tissue
distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-
14, i.e. 14C,
are particularly useful for this purpose in view of their ease of
incorporation and
ready means of detection.
Isotopic variations of the compounds of formula (I) can generally be prepared
by
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33
conventional techniques known to those skilled in the art or by processes
analogous
to those described in the accompanying Examples and Preparations using
appropriate isotopic variations of suitable reagents.
The compounds of formula (n may be freeze-dried, spray-dried, or evaporatively
dried to provide a solid plug, powder, or film of crystalline or amorphous
material.
Microwave or radio frequency drying may be used for this purpose.
The compounds of the invention may be administered alone or in combination
with
other drugs and will generally be administered as a formulation in association
with
one or more pharmaceutically acceptable excipients. The term "excipient" is
used
herein to describe any ingredient other than the compound of the invention.
The
choice of excipient will to a large extent depend on the particular mode of
administration.
The compounds of the invention may be administered in combination,
separately, simultaneously or sequentially, with one or more other
pharmacologically active agents. Suitable agents, particularly for the
treatment
of pain, include:
(i) opioid analgesics, e.g. morphine, heroin, hydromorphone, oxymorphone,
levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine,
codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene,
nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol,
nalbuphine and pentazocine;
(ii) nonsteroidal antiinflammatory drugs (NSA~s), e.g. aspirin, diclofenac,
diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,
flurbiprofen,ibuprofen,
indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid,
nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac,
tolmetin, zomepirac, and their pharmaceutically acceptable salts;
(iii) barbiturate sedatives, e.g. amobarbital, aprobarbital, butabarbital,
butabital,
mephobarbital, metharbital, methohexital, pentobarbital, phenobartital,
secobarbital, talbutal, theamylal, thiopental and their pharmaceutically
acceptable salts;
(iv) benzodiazepines having a sedative action, e.g. chlordiazepoxide,
clorazepate,
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diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam and
their pharmaceutically acceptable salts,
(v) Hl antagonists having a sedative action, e.g. diphenhydramine, pyrilamine,
promethazine, chlorpheniramine, chlorcyclizine and their pharmaceutically
acceptable salts;
(vi) miscellaneous sedatives such as glutethimide, meprobamate, methaqualone,
dichloralphenazone and their pharmaceutically acceptable salts;
(vii) skeletal muscle relaxants, e.g. baclofen, carisoprodol, chlorzoxazone,
cyclobenzaprine, methocarbamol, orphrenadine and their pharmaceutically
acceptable salts,
(viii) alpha-2-delta ligands, e.g. gabapentin and pregabalin;
(ix) alpha-adrenergic active compounds, e.g. doxazosin, tamsulosin, clonidine
and 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2, 3,4-
tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;
(x) tricyclic antidepressants, e.g. desipramine, imipramine, amytriptiline and
nortriptiline;
(xi) anticonvulsants, e.g. carbamazepine and valproate;
(xii) serotonin reuptake inhibitors, e.g. fluoxetine, paroxetine, citalopram
and
sertraline;
(xiii) mixed serotonin-noradrenaline reuptake inhibitors, e.g. milnacipran,
venlafaxine and duloxetine;
(xiv) noradrenaline reuptake inhibitors , e.g. reboxetine;
(xv) Tachykinin (NK) antagonists, particularly Nk-3, NK-2 and NK-1
antagonists,
e.g. (aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl] -8,9,10,11-tetrahydro-9-
methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthridine-6-13-
dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-
bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-
morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869),
lanepitant, dapitant and 3-[ [2-methoxy-5-
(trifluoromethoxy)phenyl]methylamino]-2-phenyl-piperidine (2S,3S)
(xvi) Muscarinic antagonists, e.g oxybutin, tolterodine, propiverine, tropsium
chloride and darifenacin;
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(xvii) COX-2 inhibitors, e.g. celecoxib, rofecoxib and valdecoxib;
(xviii) Non-selective COX inhibitors (preferably with GI protection), e.g.
nitroflurbiprofen (HCT-1026);
(xix) coal-tar analgesics, in particular, paracetamol;
5 (xx) neuroleptics, such as droperidol;
(xxi) Vanilloid receptor agonists, e.g. resinferatoxin;
(xxii) Beta-adrenergic compounds such as propranolol;
(xxiii) Local anaesthetics, such as mexiletine;
(xxiv) Corticosteriods, such as dexamethasone
10 (xxv) serotonin receptor agonists and antagonists;
(xxvi) cholinergic (nicotinic) analgesics; and
(xxvii) miscellaneous analgesic agents, such as Tramadol~.
Thus, the invention further provides a combination comprising a compound
15 of the invention or a pharmaceutically acceptable salt, solvate or pro-drug
thereof,
and a compound or class of compounds selected from the group (i)-(xxvii),
above.
There is also provided a pharmaceutical composition comprising such a
combination,
together with a pharmaceutically acceptable excipient, diluent or carrier,
particularly
for the treatment of a disease for which an alpha-2-delta ligand is
implicated.
20 Combinations of the compounds of the present invention and other
therapeutic agents may be administered separately, sequentially or
simultaneously.
Thus, the present invention extends to a kit comprising a compound of the
invention,
one or more other therapeutic agents, such as those listed above, and a
suitable
container.
25 The compounds of the present invention may be formulated by any
convenient means using well-known carriers and excipients. Thus, the present
invention also provides a pharmaceutical composition comprising a compound of
the invention or a pharmaceutically acceptable ester or a pharmaceutically
acceptable salt thereof with one or more pharmaceutically acceptable carriers.
ORAL ADMINISTRATION
The compounds of the invention may be administered orally. Oral administration
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36
may involve swallowing, so that the compound enters the gastrointestinal
tract, or
buccal or sublingual administration may be employed by which the compound
enters
the blood stream directly from the mouth.
Formulations suitable for oral administration include solid formulations such
as
tablets, capsules containing particulates, liquids, or powders, lozenges
(including
liquid-filled), chews, multi- and nano-particulates, gels, films (including
muco-
adhesive), ovules, sprays and liquid formulations.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such
formulations may be employed as fillers in soft or hard capsules and typically
comprise a carrier, for example, water, ethanol, propylene glycol,
methylcellulose,
or a suitable oil, and one or more emulsifying agents andlor suspending
agents.
Liquid formulations may also be prepared by the reconstitution of a solid, for
example, from a sachet.
The compounds of the invention may also be used in fast-dissolving, fast-
disintegrating dosage forms such as those described in Expert Opinion in
Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).
The composition of a typical tablet in accordance with the invention may
comprise:
Ingredient % w/w
Compound of formula (1J 10.00*
Microcrystalline cellulose 64.12
Lactose 21.38
Croscarmellose sodium 3.00
Magnesium stearate 1.50
* Quantity adjusted in accordance with drug activity.
A typical tablet may be prepared using standard processes known to a
formulation
chemist, for example, by direct compression, granulation (dry, wet, or
melt), melt congealing, or extrusion. The tablet formulation may comprise one
or
more layers and may be coated or uncoated.
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37
Examples of excipients suitable for oral administration include carriers, for
example,
cellulose, calcium carbonate, dibasic calcium phosphate, mannitol and
sodium citrate, granulation binders, for example, polyvinylpyrrolidine,
hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin,
disintegrants,
for example, sodium starch glycolate and silicates, lubricating agents, for
example,
magnesium stearate and stearic acid, wetting agents, for example, sodium
lauryl
sulphate, preservatives, anti-oxidants, flavours and colourants.
Solid formulations for oral administration may be formulated to be immediate
and/or modified release. Modified release formulations include delayed-,
sustained-,
pulsed-, controlled dual-, targeted and programmed release. Details of
suitable
modified release technologies such as high energy dispersions, osmotic and
coated
particles are to be found in Verma et al, Pharmaceutical Technology On-line,
25(2),
1-14 (2001). Other modified release formulations are described in US Patent
No.
6,106,864.
PARENTERAL ADMINISTRATION
The compounds of the invention may also be administered directly into the
blood
stream, into muscle, or into an internal organ. Suitable means for parenteral
administration include intravenous, intraarterial, intraperitoneal,
intrathecal,
intraventricular, intraurethral, intrasternal, intracranial, intramuscular and
subcutaneous. Suitable devices for parenteral administration include needle
(including microneedle) injectors, needle-free injectors and infusion
techniques.
Parenteral formulations are typically aqueous solutions which may contain
excipients such as salts, carbohydrates and buffering agents (preferably to a
pH of
from 3 to 9), but, for some applications, they may be more suitably formulated
as a
sterile non-aqueous solution or as a dried form to be used in conjunction with
a
suitable vehicle such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, for
example, by
lyophilisation, may readily be accomplished using standard pharmaceutical
techniques well known to those skilled in the art.
The solubility of compounds of formula (I) used in the preparation of
parenteral
solutions may be increased by suitable processing, for example, the use of
high
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38
energy spray-dried dispersions (see WO 01/47495) and/or by the use of
appropriate
formulation techniques, such as the use of solubility-enhancing agents.
Formulations for parenteral administration may be formulated to be immediate
and/or modified release. Modified release formulations include delayed-,
sustained-,
pulsed-, controlled dual-, targeted and programmed release.
TOPICAL ADMINISTRATION
The compounds of the invention may also be administered topically to the skin
or
mucosa, either dermally or transdermally. Typical formulations for this
purpose
include gels, hydrogels, lotions, solutions, creams, ointments, dusting
powders,
dressings, foams, films, skin patches, wafers, implants, sponges, fibres,
bandages
and microemulsions. Liposomes may also be used. Typical carriers include
alcohol,
water, mineral oil, liquid petrolatum, white petrolatum, glycerin and
propylene
glycol. Penetration enhancers may be incorporated - see, for example, J Pharm
Sci,
88 (10), 955-958 by Finnin and Morgan (October 1999).
Other means of topical administration include delivery by iontophoresis,
electroporation, phonophoresis, sonophoresis and needle-free or microneedle
injection.
Formulations for topical administration may be formulated to be immediate
and/or
modified release. Modified release formulations include delayed-, sustained-,
pulsed-, controlled dual-, targeted and programmed release. Thus compounds of
the invention may be formulated in a more solid form for administration as an
implanted depot providing long-term release of the active compound.
INHALED/INTRANASAL ADMINISTRATION
The compounds of the invention can also be administered intranasally or by
inhalation, typically in the form of a dry powder (either alone, as a mixture,
for
example, in a dry blend with lactose, or as a mixed component particle, for
example,
mixed with phospholipids) from a dry powder inhaler or as an aerosol spray
from a
pressurised container, pump, spray, atomiser (preferably an atomiser using
electrohydrodynamics to produce a fine mist), or nebuliser, with or without
the use
of a suitable propellant, such as dichlorofluoromethane.
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39
The pressurised container, pump, spray, atomizer, or nebuliser contains a
solution or
suspension of the active compound comprising, for example, ethanol
(optionally,
aqueous ethanol) or a suitable alternative agent for dispersing, solubilising,
or
extending release of the active, the propellants) as solvent and an optional
surfactant, such as sorbitan trioleate or an oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is
micronised to a size suitable for delivery by inhalation (typically less than
5
microns). This may be achieved by any appropriate comminuting method, such as
spiral jet milling, fluid bed jet milling, supercritical fluid processing to
form
nanoparticles, high pressure homogenisation, or spray drying.
A suitable solution formulation for use in an atomiser using
electrohydrodynamics
to produce a fine mist may contain from 1 ~,g to l Omg of the compound of the
invention per actuation and the actuation volume may vary from 1 ~.1 to 1001.
A
typical formulation may comprise a compound of formula (I), propylene glycol,
sterile water, ethanol and sodium chloride. Alternative solvents which may be
used
instead of propylene glycol include glycerol and polyethylene glycol.
Capsules, blisters and cartridges (made, for example, from gelatin or HPMC)
for use
in an inhaler or insufflator may be formulated to contain a powder mix of the
compound of the invention, a suitable powder base such as lactose or starch
and a
performance modifier such as l-leucine, mannitol, or magnesium stearate.
In the case of dry powder inhalers and aerosols, the dosage unit is determined
by
means of a valve which delivers a metered amount. Units in accordance with the
invention are typically arranged to administer a metered dose or "puff'.
Formulations for inhaled/intranasal administration may be formulated to be
immediate and/or modified release. Modified release formulations include
delayed-,
sustained-, pulsed-, controlled dual-, targeted and programmed release.
RECTAL/INTRAVAGINAL ADMINISTRATION
The compounds of the invention may be administered rectally or vaginally, for
example, in the form of a suppository, pessary, or enema. Cocoa butter is a
traditional suppository base, but various alternatives may be used as
appropriate.
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Formulations for rectal/vaginal administration may be formulated to be
immediate
and/or modified release. Modified release formulations include delayed-,
sustained-,
pulsed-, controlled dual-, targeted and programmed release.
5 OCULAR/ANDIAL ADMINISTRATION
The compounds of the invention may also be administered directly to the eye or
ear,
typically in the form of drops of a micronised suspension or solution in
isotonic, pH-
adjusted, sterile saline. Other formulations suitable for ocular and andial
administration include ointments, biodegradable' (e.g. absorbable gel sponges,
10 collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses
and
particulate or vesicular systems, such as niosomes or liposomes. A polymer
such as
crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a
cellulosic
polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or
methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum,
may
15 be incorporated together with a preservative, such as benzalkonium
chloride. Such
formulations may also be delivered by iontophoresis.
Formulations for ocular/andial administration may be formulated to be
immediate
and/or modified release. Modified release formulations include delayed-,
sustained-,
pulsed-, controlled dual-, targeted, or programmed release.
ENABLING TECHNOLOGIES
The compounds of the invention may be combined with soluble macromolecular
entities such as cyclodextrin or polyethylene glycol-containing polymers to
improve
their solubility, dissolution rate, taste-masking, bioavailability and/or
stability.
Drug-cyclodextrin complexes, for example, are found to be generally useful for
most
dosage forms and administration routes. Both inclusion and non-inclusion
complexes may be used. As an alternative to direct complexation with the drug,
the
cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent,
or
solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma
cyclodextrins, examples of which may be found in International Patent
Applications
Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
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41
DOSAGE
The compounds of the invention can be administered via either the oral,
parenteral
or topical routes to mammals. In general, these compounds are most desirably
administered to humans in doses ranging from 0.1 mg to 3000 mg, preferably
from 1
mg to 500 mg, which may be administered in a single dose or in divided doses
throughout the day, although variations will necessarily occur depending upon
the
weight and condition of the subject being treated, the disease state being
treated and
the particular route of administration chosen.
These dosages are based on an average human subject having a weight of about
65
to 70kg. The physician will readily be able to determine doses for subjects
whose
weight falls outside this range, such as infants and the elderly.
For example, a dosage level that is in the range of from 0.01 mg to 10 mg per
kg of
body weight per day is most desirably employed for treatment of pain
associated
with inflammation.
Examples
The invention is illustrated in the following non-limiting examples in which,
unless stated otherwise: all operations were carried out at room or ambient
temperature, that is, in the range of 18-25 °C; evaporation of solvent
was carried out
using a rotary evaporator under reduced pressure with a bath temperature of up
to 60
°C; reactions were monitored by thin layer chromatography (tlc) and
reaction times
are given for illustration only; melting points (m.p.) given are uncorrected
(polymorphism may result in different melting points); the structure and
purity of all
isolated compounds were assured by at least one of the following techniques:
tlc
(Merck silica gel 60 F25ø precoated TLC plates or Merck NHZ FZS4s precoated
HPTLC plates), mass spectrometry, nuclear magnetic resonance (NMR), infrared
red
absorption spectra (IR) or microanalysis. Yields are given for illustrative
purposes
only. Flash column chromatography was carried out using Merck silica gel 60
(230-400 mesh ASTM) or Fuji Silysia Chromatorex" DU3050 (Amino Type, 3050
~.m). Low-resolution mass spectral data (E1) were obtained on a Automass 120
(JEOL) mass spectrometer. Low-resolution mass spectral data (ESI) were
obtained
on a Quattro II (Micromass) mass spectrometer. Melting point was obtained
using
Seiko Instruments Inc. Exstar 6000. NMR data was determined at 270 MHz
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42
(JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA300) using
deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent
unless
indicated otherwise, relative to tetramethylsilane (TMS) as internal standard
in parts
per million (ppm); conventional abbreviations used are: s = singlet, d =
doublet, t =
triplet, q = quartet, m = multiplet, br. = broad, etc. IR spectra were
measured by a
Shimazu infrared spectrometer (IR-470). Optical rotations were measured using
a
JASCO DIP-370 Digital Polarimeter (Japan Spectroscopic CO, Ltd.).
Chemical symbols have their usual meanings; b.p. (boiling point), m:p.
(melting point), 1 (liter(s)), ml (milliliter(s)), g (gram(s)),
mg(milligram(s)), mol
(moles), mmol (millimoles), eq. (equivalent(s)).
Example 1
1-f 2-(3-Fluoro-4-hydrox~phenyl)-2-hydroxyethyll-4-(6-methoxypyridin-3-yl)-
piperidin-4-of methanesulfonate
1-A: 1-f4-(Benz~y -3-fluorophenyll-2-chloroethanone
To a stirred solution of 2-chloro-1-(3-fluoro-4-hydroxyphenyl)ethanone (J.
Am. Chem. Soc., 1937, 59, 280)(3.00 g, 15.9 mmol) and potassium carbonate
(4.40 g,
31.8 mmol) in acetone (100 mL) was added benzyl bromide (1.91 mL, 16.1 mmol)
at room temperature, and the mixture was stirred at room temperature
overnight.
After all solvents were removed, the residue was diluted with ethyl acetate.
The
mixture was washed with H20, dried and evaporated. The residue was purified by
chromatography on silica gel, eluting with methyl ethyl acetate / hexane (1: 5
v/v),
to afford the titled compound as a yellow solid (750 mg, 17%).
1H NMR (270 MHz, CDC13) S = 7.77-7.64 (m, 2H), 7.46-7.34 (m, 5H), 7.10-7.03
(m, 1H), 5.23 (s, 2H), 4.61 (s, 2H) ppm.
MS (E1); M+=278
1-B: tart-Butyl 4-hydroxy-4-(6-methoxypyridin-3-~piperidine-1-
carboxylate
A solution of 5-bromo-2-methoxypyridine (36 g, 193 mmol) in diethyl ether
(200 mL) was added dropwise to a solution of n-butyl lithium in hexane (1.59M,
121 mL) and diethyl ether (500 mL) at -78°C. After addition was
completed, the
mixture was stirred at -78°C for 30 minitus and to the mixture was
added a solution
of tart-butyl 4-oxopiperidine-1-carboxylate in diethyl ether (300 mL) at -
78°C. The
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43
mixture was allowed to warm to room temperature and stirred overnight. To the
mixture was added water (400 mL) and the organic layer was extracted with
diethyl
ether (500 mL). The combined organic layer was washed with brine and dried
over
NaS04 and concentrated. The residue was purified by column chromatography on
silica gel, eluting with methyl ethyl acetate l hexane (l: 2 v/v), to afford
the titled
compound (16.5g, 42%) as oil.
1-C: 4-(6-Methoxyp~ridin-3-~piperidin-4-of dihydrochloride
To a stirred solution of tert-butyl 4-hydroxy-4-(6-methoxypyridin-3
yl)piperidine-1-carboxylate (15g, 49mmo1) in ethyl acetate (300 mL) was added
4N
hydrochloride in ethyl acetate (45 mL, 150 mmol) and the resulting suspension
was
stirred at 50 °C for 2 hours. To the suspension was added additional 4N
hydrochloride in ethyl acetate (27.5 mL, 75 mmol) and stirred at 50~C for 3h.
After
cooling, the precipitate was collected and dried in vacuo for 1 hour to afford
the
titled compound as a white solid (12.7 g, 93%).
1H NMR (300 MHz, DMSO-d6) & = 9.25-8.90 (br, 2H), 8.24 (dd, J = 0.5, 2.6Hz,
1H), 7.79 (dd, J= 2.6, 8.6Hz, 1H), 6.87 (d, J= 8.6 Hz, 1H), 6.00-5.40 (br,
1H), 3.86
(s, 3H), 3.30-3.00 (m, 4H), 2.30-2.10 (m, 2H), 1.86-1.76 (m, 2H) ppm.
1-D: 1-f4-(Benzyloxy)-3-fluorophenyll-2-f4-h day-4-(6-
methoxypyridin-3-yl)- piperidin-1-yllethanone
To a stirred solution of 1-[4-(benzyloxy)-3-fluorophenyl]-2-chloroethanone
(750 mg, 2.69 mmol) in ethanol (20 mL) were added 4-(6-methoxypyridin-3-
yl)piperidin-4-of dihydrochloride (908 mg, 3.23 mmol) at room temperature
under
nitrogen and the mixture was stirred under reflux for 5 hours. After all
solvents were
removed, the residue was diluted with ethyl acetate. The mixture was washed
with
H20 and the organic layer was dried and evaporated to afford the titled
compound as
a yellow solid (1.16 g, 96°70).
1H NMR (270 MHz, DMSO-d6) 8 = 8.24 (d, J--2.5 Hz, 1H), 7.92-7.82 (m, 2H), 7.77
(dd, J--8.6, 2.5 Hz, 1H), 7.52-7.32 (m, 6H), 6.75 (d, J--8.6 Hz, 1H), 5.30 (s,
2H),
4.90 (s, 1H), 3.82 (s, 3H), 3.78 (s, 2H), 2.71-2.48 (m, 4H), 1.98-1.84 (m,
2H), 1.68
1.56 (m, 2H) ppm.
MS (ESA; (M+H)+ = 451.17, (M-H)- =449.24
1-E: 1-~2-f4-(Benzyloxy)-3-fluorophen l~h d~ rox~yl~-4-(6-
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44
methoxypyridin-3-~piperidin-4-of
To a stirred solution of sodium borohydride (146 mg, 3.86 mmol) in ethanol
(45 mL) was added suspension of 1-[4-(benzyloxy)-3-fluorophenyl]-2-[4-hydroxy-
4-
(6-methoxypyridin-3-yl)piperidin-1-yl]ethanone (1.16 g, 2.57 mmol) in ethanol
(5
mL) at 0 °C and the mixture was stirred at room temperature for 2.5
hours. After all
solvents were removed, the residue was diluted with dichloromethane. The
mixture
was washed with H20, dried and evaporated. The residue was purified by
chromatography on silica gel, eluting with methyl alcohol / dichloromethane
(1:20
v/v), to afford the titled compound as a yellow solid (648 mg, 53%).
1H NMR (270 MHz, DMSO-d6) 8 = 8.23 (d, ,1--2.5 Hz, 1H), 7.77 (dd, J--8.7, 2.5
Hz,
1H), 7.50-7.06 (m, 8H), 6.76 (d, J--8.7 Hz, 1H), 5.16 (s, 2H), 4.87 (s, 1H),
4.70-4.63
(m, 1H), 3.83 (s, 3H), 2.80-2.38 (m, 6H), 2.00-1.84 (m, 2H), 1.66-1.54 (m, 2H)
ppm.
MS (ESA; (M+H)+ = 453.19
1-F: 1-f2-(3-Fluoro-4-hydroxyphenyl)-2-h d~~yll-4-(6-
methoxypyridin-3-yl)- piperidin-4-of
A mixture of 1-{2-[4-(benzyloxy)-3-fluorophenyl]-2-hydroxyethyl}-4-(6-
methoxypyridin-3-yl)piperidin-4-of (640 mg, 1.41 mmol) and palladium, 10 wt%
on
activated carbon (300 mg) in methanol (20 mL) and acetic acid (5 mL) was
stirred
under H2 atmosphere for 26 hours. The mixture was filtered through Celite, and
the
filtrate was concentrated. The residue was purified by chromatography on
silica gel,
eluting with methyl alcohol / dichloromethane (1:15 v/v), to afford the titled
compound as a white solid (350 mg, 68%).
1H NMR (270 MHz, DMSO-d6) 8 = 9.63 (s, 1H), 8.23 (d, J--2.5 Hz, 1H), 7.77 (dd,
J--8.7, 2.5 Hz, 1H), 7.09 (d, J--12.2 Hz, 1H), 7.14-6.82 (m, 2H), 6.75 (d, J--
8.7 Hz,
1H), 4.85 (br.s, 2H), 4.65-4.54 (m, 1H), 3.82 (s, 3H), 2.71-1.55 (m, 10H) ppm.
1-G: 1-f2-(3-Fluoro-4-hydroxyphenyl)-2-h dr~oxyethyll-4-(6-
methoxypyridin-3-yl)-piperidin-4-of methanesulfonate
Methanesulfonic acid (26.1 ~,L, 0.389 mmol) was added to a solution of 1-
[2-(3-fluoro-4-hydroxyphenyl)-2-hydroxyethyl]-4-(6-methoxypyridin-3-
yl)piperidin-
4-0l (141 mg, 0.389 mmol) in methyl alcohol (3 mL). The mixture was stirred
for 30
minutes at room temperature and filtered. The filtrate was evaporated and the
residue was crystallized from ethanol-diisopropylether to afford the titled
compound
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WO 2005/035522 PCT/IB2004/003127
as a white amorphous (81 mg, 45%).
1H NMR (270 MHz, DMSO-d6) 8 = 9.90 (s, 1H), 9.26 (s, 1H), 8.25 (d, J--2.3 Hz,
1H), 7.77 (dd, J--8.7, 2.3 Hz, 1H), 7.26-6.80 (m, 4H), 5.10-5.00 (m, 1H), 3.85
(s,
3H), 3.82-3.16 (rn, 8H), 2.34 (s, 3H), 2.42-2.09 (m, 2H), 1.97-1.74 (m, 2H)
ppm
5 MS (ESA; (M+H)+ = 363.11, (M-H)- = 361.16
IR (I~Br); 3359, 1670 cm 1
Example 2
4-(3,4-Dihydro-1H isochromen-7-yl)-1-f2-(3-fluoro-4-h d~yphenyl)-2-
h d~roxyethyllpiperidin-4-of methanesulfonate
10 2-A: Ether 4-(3,4-dihydro-1H isochromen-7- l~ydroxypiperidine-1-
carboxylate
To a solution of 7-bromoisochroman (WO 9305772 Al) (5.3 g, 25 mmol) in
tetrahydrofuran (35 mL) was added 1.5 M solution of n-butyllithium in hexane
(17
mL, 26 mmol) dropwise at -78 °C. The mixture was stirred at -78
°C for 1 hour.
15 To this mixture was added a solution of N carbethoxy-4-piperidone (4.3 g,
25
mmol) in tetrahydrofuran (35 mL) at -78 °C. The mixture was stirred at -
78 °C for
an additional 1 hour and warmed to room temperature. Water (30 mL,) was
carefully added to the mixture and the organic layer was separated. The
aqueous
layer was extracted with ethyl acetate (30 mL x2). The combined organic layers
20 were washed with saturated aqueous sodium chloride solution, dried over
potassium
carbonate, filtered and concentrated under reduced pressure to give 7.8 g of a
white
powder. The powder was washed with 2-propanol to give the titled compound as a
white powder (5.7 g, 75%).
1H NMR (270 MHz, CDCl3) 8 = 7.36-7.08 (m, 3H), 4.77 (s, 2H), 4.31-3.93 (m,
4H),
25 4.16 (q, J = 7.1 Hz, 2H), 3.44-3.20 (m, 2H), 2.93-2.80 (m, 2H), 2.09-1.91
(m, 2H),
1.81-1.67 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H) ppm.
2-B: 4-(3,4-Dihydro-1H isochromen-7-yl)piperidin-4-of
To a suspension of ethyl 4-(3,4-dihydro-1H isochromen-7-yl)-4
hydroxypiperidine-1-carboxylate (5.7 g, 19 mmol) in ethanol (6.3 mL) was added
30 potassium hydroxide (5.3 g, 94 mmol). The mixture was stirred under reflux
for 2
hours. The mixture was concentrated under reduced pressure. The residue was
diluted with dichloromethane (20 mL) and the resulting suspension was washed
with
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46
water (20 mL). The organic layer was separated and the aqueous layer was
extracted with dichloromethane (20 mL x 2). The combined organic layers were
washed with brine, dried over potassium carbonate, filtered and concentrated
under
reduced pressure to give the titled compound as a pale yellow color solid (3.9
g,
89°7o).
1H NMR,(270 MHz, CDC13) & = 7.38-7.23 (m, 1H), 7.20-7.02 (m, 2H), 4.77 (s,
2H),
4.03-3.90 (m, 2H), 3.20-3.02 (m, 2H), 3.00-2.77 (m, 4H), 2.12-1.90 (m, 2H),
1.87-
1.58 (m, 2H) ppm.
2-C: 2-f4-(3,4-Dihydro-1H isochromen-7-" 1~, droxypiperidin-1-yll-1-(3-
fluoro-4-h,~yphenyl)ethanone
The title compound was prepared according to the procedure described in
Example 1 from 2-chloro-1-(3-fluoro-4-hydroxyphenyl)ethanone and 4-(3,4-
dihydro-1H isochromen-7-yl)piperidin-4-ol: 1.26 g (100%) as yellow solid.
1H NMR (300 MHz, DMSO-d6) S = 7.80-7.70 (m, 2H), 7.28-6.96 (m, 4H), 4.70
4.60 (m, 3H), 3.86 (t, J=5.7 Hz, 2H), 2.80-2.46 (m, 8H), 1.98-1.82 (m, 2H),
1.60
1.50 (m, 2H) ppm.
MS (ESn; (M+H)+ = 386.10, (M-H)- = 384.18
2-D: 2-~4-(3,4-Dihydro-1H isochromen-7-, l~ydroxypiperidin-1-yll-1-~3-
fluoro-4-~(triisoproRylsilyl)oxy]_phenyll ethanone
To a stirred solution of 2-[4-(3,4-dihydro-1H isochromen-7-yl)-4-
hydroxypiperidin-1-yl]-1-(3-fluoro-4-hydroxyphenyl)ethanone (1.26 g, 2.65
mmol)
and triethylamine (1.1l mL, 7.96 mmol) in tetrahydrofuran (100 mL) was added
triisopropylsilyl chloride (0.624 mL, 2.92 mmol) at room temperature, and the
mixture was stirred at room temperature for 2.5 hours. The mixture was treated
with
H20 and extracted with ethyl acetate. The combined organic layer was dried and
evaporated to afford the titled compound as a yellow solid (1.51 g quant.).
1H NMR (300 MHz, CDC13) ~ = 7.78 (dd, J--11.3, 2.2 Hz, 1H), 7.75-7.70 (m, 1H),
7.34-7.28 (m, 1H), 7.16-7.10 (m, 2H), 6.98 (t, J--8.4 Hz, 1H), 4.77 (s, 2H),
3.97 (t,
J--5.7 Hz, 2H), 3.81 (br.s, 3H), 2.94-2.58 (m, 6H), 2.32-2.18 (m, 2H), 1.80-
1.68 (m,
2H), 1.40-1.20 (m, 3H), 1.11 (d, J--7.1 Hz, 18H) ppm.
MS (ESA; (M+H)+ = 542.25
2-E: 4-(3,4-Dihydro-1H isochromen-7-yl)-1-(2-(3-fluoro-4-
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47
f (triisopro~ylsilyl)-ox~phen l~ drox~ethyl)piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 2-[4-(3,4-dihydro-1H isochromen-7-yl)-4-hydroxypiperidin-1-yl]
1-{3-fluoro-4-[(triisopropylsilyl)oxy]phenyl}ethanone: 907 mg (63%) as yellow
solid.
1H NMR (300 MHz, DMSO-d6) 8 = 7.24 (dd, J--7.9, 1.7 Hz, 1H), 7.17 (dd, ,1--
12.1,
1.7 Hz, 1H), 7.12 (br.s, 1H), 7.08-7.01 (m, 2H), 6.94 (t, J--8.6 Hz, 1H), 4.99
(s, 1H),
4.72-4.60 (m, 4H), 3.86 (t, J--5.5 Hz, 2H), 2.78-2.36 (m, 8H), 1.96-1.80 (m,
2H),
1.54-1.49 (m, 2H), 1.34-1.14 (m, 3H), 1.06 (d, J--7.0 Hz, 18H) ppm.
MS (ESn; (M+H)+ = 544.25
2-F: 4-(3,4-Dihydro-1H isochromen-7-xl)-1-f2-(3-fluoro-4-
~droxyphenyl)-2-hydroxyethyllpiperidin-4-of
A mixture of 4-(3,4-dihydro-1H isochromen-7-yl)-1-(2-{3-fluoro-4-
[(triisopropylsilyl)oxy]phenyl}-2-hydroxyethyl)piperidin-4-of (907 mg, 1.67
mmol)
and tetrabutylammonium fluoride (435 mg, 1.67 mmol) in tetrahydrofuran (15 mL)
was stirred at room temperature for ~1.5 hours. After all solvents were
removed, the
residue was purified by chromatography on silica gel, eluting with
triethylamine /
ethyl acetate / hexane (0.05:1:2 v/v/v), to afford the titled compound as a
white solid
(484 mg, 75%).
1H NMR (270 MHz, DMSO-d6) 8 = 9.61 (br.s, 1H), 7.25 (d, J--8.1 Hz, 1H), 7.14-
7.01 (m, 3H), 6.99-6.84 (m, 2H), 4.70-4.58 (m, 4H), 3.89-3.82 (m, 2H), 2.76-
2.35
(m, 9H), 2.00-1.80 (m, 2H), 1.60-1.48 (m, 2H) ppm.
2-G: 4-(3,4-Dihydro-1H isochromen-7-yl)-1-f2-(3-fluoro-4-
hydroxyphenyl)-2-h~~thyllpiperidin-4-of methanesulfonate
By the procedures of example 1, 4-(3,4-dihydro-1H isochromen-7-yl)-1-[2-
(3-fluoro-4-hydroxyphenyl)-2-hydroxyethyl]piperidin-4-of was converted to the
title
compound obtained as a white amorphous in 89% (536 mg) after crystallization
from ethanol-diisopropylether.
1H NMR (270 MHz, DMSO-d6) 8 = 9.91 (s, 1H), 9.21 (s, 1H), 7.39-6.94 (m, 6H),
5.05-5.01 (m, 1H), 4.70 (s, 2H), 3.88 (t, J--5.8 Hz, 2H), 3.62-3.23 (m, 6H),
2.76 (t,
J--5.8 Hz, 2H), 2.43-2.22 (m, 2H), 2.33 (s, 3H), 1.86-1.76 (m, 2H) ppm.
MS (ESn; (M+H)+ = 388.14, (M-H)- = 386.20
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WO 2005/035522 PCT/IB2004/003127
48
IR (KBr); 3265 cm 1
Example 3
1-f2-(3-Fluoro-4-hydroxyphen l~ydrox~ethyll-4-(3-Buorophen~piperidin-4-of
methanesulfonate
3-A: 1-(3-Fluoro-4-hydrox henyl)-2-f4-(3-fluorophenyl)-4-
~droxypi~eridin-1-yllethanone
The title compound was prepared according to the procedure described in
Example
1 from 2-chloro-1-(3-fluoro-4-hydroxyphenyl)ethanone and 4-(3-
fluorophenyl)piperidin-4-of (US 4292321): 644 mg (70%) as yellow solid.
1H NMR (270 MHz, DMSO-d6) ~ = 7.67-6.70 (m, 7H), 3.60-2.60 (m, 6H), 2.04-
1.88 (m, 2H), 1.66-1.50 (m, 2H) ppm.
MS (ES)]; (M+H)+ = 348.03
3-B: 2-f4-(3-Fluorophen l~ydroxypiperidin-1-yll-1-~3-fluoro-4-
f (triisopropylsilyl)oxylphenyl 1 ethanone
The title compound was prepared according to the procedure described in
Example 2 from 1-(3-fluoro-4-hydroxyphenyl)-2-[4-(3-fluorophenyl)-4-
hydroxypiperidin-1-yl]ethanone: 1.38 g (95%) as yellow solid.
1H NMR (300 MHz, DMSO-d6) 8 = 7.90-7.78 (m, 2H), 7.40-7.22 (m, 3H), 7.13 (t,
J--8.6 Hz, 1H), 7.06-6.98 (m, 1H), 4.97 (s, 1H), 3.80 (s, 2H), 2.73-2.50 (m,
4H),
2.00-1.88 (m, 2H), 1.62-1.53 (m, 2H), 1.40-1.23 (m, 3H), 1.07 (d, J--7.1 Hz,
18H)
ppm.
MS (ES)); (M+H)+ = 504.22
C. 4-l3-Fluoronhenvll-1-l2-( 3-fluoro-4-f (triisonronvlsilvlloxvluhenvll-2-
h dy rox, e~thyl)piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 2-[4-(3-fluorophenyl)-4-hydroxypiperidin-1-yl]-1-{3-fluoro-4-
[(triisopropylsilyl)oxy]phenyl}ethanone: 1.05 g (64%) as yellow solid.
1H NMR (300 MHz, CDCl3) ~ = 7.38-7.20 (m, 3H), 7.10 (t, J--11.7, 2.0 Hz, 1H),
7.00-6.88 (m, 3H), 4.68 (dd, J--10.4, 3.5 Hz, 1H), 3.08-1.74 (m, 10H), 1.35-
1.17 (m,
3H), 1.10 (d, J--6.8 Hz, 18H) ppm.
MS (ESI); (M+H)+ = 506.22
3-D: 1-f 2-(3-Fluoro-4-hYdroxxphenyl)-2-h~x~thyll-4-(3-fluorophenyl)-
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49
piperidin-4-of
The title compound was prepared according to the procedure described in
Example 2 from 4-(3-fluorophenyl)-1-(2-{3-fluoro-4
[(triisopropylsilyl)oxy]phenyl}-2-hydroxyethyl)piperidin-4-ol: 420 mg (58%) as
a
white solid.
1H NMR (270 MHz, DMSO-d6) 8 = 9.63 (s, 1H), 7.40-7.23 (m, 3H), 7.12-6.86 (m,
4H), 4.91 (br.s, 2H), 4.65-4.54 (m, 1H), 2.76-2.46 (m, 6H), 1.97-1.88 (m, 2H),
1.60-
1.50 (m, 2H) ppm.
3-E: 1-f2-(3-Fluoro-4-h droxyphen 1~ d~~yll-4-(3-fluorophenyl)-
~peridin-4-of methanesulfonate
By the procedures of example 1, 1-[2-(3-fluoro-4-hydroxyphenyl)-2-
hydroxyethyl]-4-(3-fluorophenyl)piperidin-4-of was converted to the title
compound
obtained as a white solid in 60% (320 mg) after recrystallization from ethanol-
diisopropylether.
1H NMR (270 MHz, DMSO-d6) b = 9.23 (s, 1H), 7.50-6.92 (m, 7H), 5.10-5.00 (m,
1H), 3.80-3.19 (m, 9H), 2.41-2.20 (m, 2H), 2.35 (s, 3H), 1.92-1.66 (m, 2H)
ppm.
MS (ESI]; (M+H)+ = 350.08, (M-H)- = 348.13
IR (I~Br); 3429, 1622 cm 1
Example 4
4-(3,4-Dihydro-1H-isochromen-7-yl)-1-f2-hydroxy-2-(4-hydroxy-3-
methylphenyl)ethyllpiperidin-4-of
4-A: 1-f4-(Benzyloxy)-3-methylphenyll-2-bromoethanone
To a stirred solution of 1-[4-(benzyloxy)-3-methylphenyl]ethanone (WO
9723216)(2.75 g, 11.4 mmol) in 1,4-dioxane (50 mL) and ethyl acetate (10 mL)
was
added bromine (0.587 mL, 11.4 mmol) at room temperature, and the mixture was
stirred at room temperature for 15 minutes. The mixture was treated with aq.
sodium
thiosulfate and extracted with ethyl acetate. The combined organic layer was
dried
and evaporated to afford the titled compound as a yellow oil (3.86 g, quant.).
1H NMR (270 MHz, CDCl3) ~ = 7.96-7.80 (m, 2H), 7.48-7.30 (m, 5H), 6.96-6.90
(m, 1H), 5.18 (s, 2H), 4.40 (s, 2H), 2.32 (s, 3H) ppm.
MS (El]; M+ = 318, 320
4-B: 1-f4-(Benzyloxy)-3-meth~phenxll-2-f4-(3,4-dihydro-1H isochromen-
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7-yl)-4-h dy roxypiperidin-1-yllethanone
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)-3-methylphenyl]-2-bromoethanone and 4-(3,4-
dihydro-1H isochromen-7-yl)piperidin-4-ol: 391 mg (42%) as a yellow solid.
5 1H NMR (270 MHz, DMSO-d6) 8 = 7.91 (d, J--8.7 Hz, 1H), 7.84 (s, 1H), 7.52-
7.30
(m, 5H), 7.25 (d, J--8.1 Hz, 1H), 7.17-7.12 (m, 2H), 7.07 (d, J--8.1 Hz, 1H),
5.25 (s,
2H), 4.80 (br.s, 1H), 4.67 (s, 2H), 3.89-3.84 (m, 6H), 2.80-2.54 (m, 4H), 2.26
(s,
3H), 2.03-1.52 (m, 4H) ppm.
MS (ESA; (M+H)+ = 472.18
10 4-C: 1-12-f4-(Benzyloxy)-3-methylphen l~ d~yethyll-4-(3,4-
dihydro-1H isochromen-7-~piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)-3-methylphenyl]-2-[4-(3,4-dihydro-1H
isochromen-7-yl)-4-hydroxypiperidin-1-yl]ethanone: 266 mg (68%) as a white
solid.
15 1H NMR (300 MHz, CDC13) ~ = 7.48-7.22 (m, 6H), 7.16-7.04 (m, 4H), 6.94 (d,
J--8.4 Hz, 1H), 5.10 (s, 2H), 4.76 (br.s, 1H), 4.70 (s, 1H), 4.67 (s, 2H),
4.67-4.59 (m,
1H), 3.86 (t, J--5.9 Hz, 2H), 2.78-2.68 (m, 4H), 2.59-2.35 (m, 4H), 2.20 (s,
3H),
2.00-1.50 (m, 4H) ppm.
4-D: 4-(3,4-Dihydro-1H isochromen-7-yl)-1-f2-h, day-2-(4-h, day-3-
20 methyl~yl)eth~piperidin-4-of
By the procedures of example 1, 1-{2-[4-(benzyloxy)-3-methylphenyl]-2-
hydroxyethyl}-4-(3,4-dihydro-1H isochromen-7-yl)piperidin-4-of was converted
to
the title compound obtained as a white solid in 60% (130 mg) after
recrystallization
from ethanol-diisopropylether.
25 1H NMR (300MHz, DMSO-d6) 8 = 9.10 (s, 1H), 7.25 (d, J--8.2 Hz, 1H), 7.13
(s,
1H), 7.06 (d, J--8.2 Hz, 1H), 7.03 (s, 1H), 6.95 (d, J--8.0 Hz, 1H), 6.70 (d,
J--B.O Hz,
1H), 4.72-4.54 (m, 5H), 3.86 (t, J--5.3 Hz, 2H), 2.80-2.34 (m, 8H), 2.10 (s,
3H),
1.98-1.50 (m, 4H) ppm.
MS (ESn; (M+H)+ = 384.14, (M-H)- = 382.23
30 m.p.178.3°C
IR (KBr); 3298, 1612 cm 1
Example 5
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4-(3-Fluorophenyl)-1-f 2-hydroxy-2-(4-hydroxy-3-methylphenyl)ethyllpiperidin-4-
of
5-A: 1-f4-Benzyloxy)-3-methylphenyll-2-[4-(3-fluorophen 1y )=4-
hydroxypiperidin-1-yllethanone
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)-3-methylphenyl]-2-bromoethanone and 4-(3-
fluorophenyl)piperidin-4-ol: 1.4 g (quant.) as an orange solid.
MS (ESI]; (M+H)+ = 434.14
5-B: 1-12-f4-Benzyloxy)-3-methylphen l~ydroxyethyl}-4-(3-
fluorophenyl)-piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)-3-methylphenyl]-2-[4-(3-fluorophenyl)-4-
hydroxypiperidin-1-yl]ethanone: 627 mg (45%) as a yellow solid.
1H NMR (300 MHz, DMSO-d6) ~ = 7.47-6.93 (m, 12H), 5.11 (s, 2H), 5.20-4.60 (m,
3H), 2.79-2.19 (m, 6H), 2.21 (s, 3H), 2.05-1.95 (m, 2H), 1.62-1.52 (m, 2H)
ppm.
MS (ESA; (M+H)+ = 436.17
5-C: 4-(3-Fluorophenyl)-1-f2-hydroxy-2-(4-hydroxy-3-
methylphen 1y )ethyll-piperidin-4-of
By the procedures of example 1, 1-{2-[4-(benzyloxy)-3-methylphenyl]-2-
hydroxyethyl}-4-(3-fluorophenyl)piperidin-4-olwas converted to the title
compound
obtained as a white solid in 72% (351 rng) after recrystallization from
ethanol-
diisopropylether.
1H NMR (300 MHz, DMSO-d6) ~ = 9.09 (s, 1H), 7.41-7.25 (m, 3H), 7.08-6.92 (m,
3H), 6.70 (d, J--8.0 Hz, 1H), 4.92 (s, 1H), 4.66 (d, J--2.7 Hz, 1H), 4.62-4.56
(m, 1H),
2.80-2.30 (m, 6H), 2.10 (s, 3H), 2.02-1.86 (m, 2H), 1.62-1.50 (m, 2H) ppm.
MS (ESn; (M+H)+ = 346.08, (M-H)- = 344.17
Example 6
1-f2-Hydroxy=2-(4-hydroxy-3-methylphen 1y )ethyll-4-(6-methoxypyridin-3-yl)-
~peridin-4-of
6-A: 1-f4-(Benzyloxy)-3-methylphenyll-2-f4-h dry-oxy-4-(6-
methoxypyridin-3-yl)-piperidin-1-yllethanone
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)-3-methylphenyl]-2-bromoethanone and 4-(6-
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52
methoxypyridin-3-yl)piperidin-4-of dihydrochloride: 683 mg (45%) as a white
solid.
1H NMR (300 MHz, DMSO-d6) 8 = 8.25(s, 1H), 7.92-7.30 (m, 8H), 7.14 (d, J--8.5
Hz, 1H), 6.77 (d, J--8.5 Hz, 1H), 5.25 (s, 2H), 5.02 (s, 1H), 3.99 (s, 2H),
3.83 (s, 3H),
2.90-2.52 (m, 4H), 2.26 (s, 3H), 2.02-1.95 (m, 2H), 1.70-1.60 (m, 2H) ppm.
MS (ESI); (M+H)+ = 447.16
6-B: 1-( 2-f 4-(Benzyloxy)-3-methylphenyll-2-hydroxyethyl ~-4-(6-
methoxypyridin-3-yl)piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)-3-methylphenyl]-2-[4-hydroxy-4-(6
methoxypyridin-3-yl)piperidin-1-yl]ethanone: 368 mg (54%) as a white solid.
MS (ESI); (M+H)+ = 449.17
6-C: 1-f2-Hydroxy-2-(4-h dy roxy-3-methylphen l~yll-4-(6-
methoxypyridin-3-yl)-pit~eridin-4-of
By the procedures of example l, 1-{2-[4-(benzyloxy)-3-methylphenyl]-2-
hydroxyethyl}-4-(3-fluorophenyl)piperidin-4-olwas converted to the title
compound
obtained as a white solid in 75% (221 mg) after recrystallization from 2-
propanol-
diisopropylether.
1H NMR (300 MHz, DMSO-d6) b = 9.09 (s, 1H), 8.24 (d, J--2.6 Hz, 1H), 7.77 (dd,
J--8.7, 2.6 Hz, 1H), 7.02 (d, J--2.0 Hz, 1H), 6.95 (dd, J--8.2, 2.0 Hz, 1H),
6.76 (d,
J--8.7 Hz, 1H), 6.69 (d, J--8.2 Hz, 1H), 4.86 (br.s, 1H), 4.66 (br.s, 1H),
4.60-4.54 (m,
1H), 3.82 (s, 3H), 2.80-2.30 (m, 6H), 2.10 (s, 3H), 2.00-1.57 (m, 4H) ppm.
MS (ESI); (M+H)+ = 359.12, (M-H)- = 357.20
m.p. 176.0°C
IR (KBr); 3197, 1608 cm 1
Example 7
1-f2-(2-Fluoro-4-hydroxyphenyl)-2-h dy rox~thyll-4-(3-fluorophenyl)piperidin-4-
of
7-A: 1-f 4-(Benz,~y)-2-fluorophenyll-2-bromoethanone
The title compound was prepared according to the procedure described in
Example 4 from 1-[4-(benzyloxy)-2-fluorophenyl]ethanone (WO 0170702): 3.70 g
(quant.) as a yellow solid.
1H NMR (300 MHz, CDC13) 8 = 7.95 (t, J--8.8 Hz, 1H), 7.45-7.35 (m, 5H), 6.92-
6.70 (m, 2H), 5.13 (s, 2H), 4.47 (d, J=2.6 Hz, 2H) ppm.
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53
MS (En; M+ = 322, 324
7-B: 1-( 2-f 4-Benzyloxyl-2-fluorophenyll-2-hydroxyeth~ ~-4-(3-
fluorophenyl)-~peridin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)-2-fluorophenyl]-2-bromoethanone and 4-(3-
fluorophenyl)piperidin-4-ol: 599m g (68%) as a white solid
1H NMR (270 MHz, DMSO-d6) 8 = 7.48-7.22 (m, 9H), 7.06-6.96 (m, 1H), 6.88-
6.80 (m, 2H), 5.11 (s, 2H), 5.02 (br.s, 1H), 4.98-4.88 (m, 1H), 4.91 (s, 1H),
2.76-
2.40 (m, 6H), 2.00-1.83 (m, 2H), 1.60-1.50 (m, 2H) ppm.
MS (ESn; (M+H)+ = 440.14
7-C: 1-f 2-(2-Fluoro-4-hydroxyphenyl)-2-hydroxyethyll-4-(3-
fluorophenyl)-~peridin-4-of
By the procedures of example 1, 1-{2-[4-(benzyloxy)-2-fluorophenyl]-2
hydroxyethyl}-4-(3-fluorophenyl)piperidin-4-of was converted to the title
compound
obtained as a white solid in 53 % (254 mg) after recrystallization from 2-
propanol.
1H NMR (300 MHz, DMSO-d6) 8 = 9.75 (br.s, 1H), 7.40-7.24 (m, 4H), 7.06-6.98
(m, 1H), 6.60 (dd, J--8.4, 2.2 Hz, 1H), 6.49 (dd, J--12.3, 2.2 Hz, 1H), 4.95-
4.88 (m,
3H), 2.78-2.65 (m, 2H), 2.60-2.30 (m, 4H), 2.00-1.85 (m, 2H), 1.62-1.50 (m,
2H)
ppm.
MS (ESA; (M+H)+ = 350.08, (M-H)- = 348.14
m.p. 186.1°C
Example 8
4-(3 4-Dihydro-1H isochromen-7-yl)-1-f2-(2-fluoro-4-hydroxyphenyl)-2-
hydrox.Yethyllpiperidin-4-of
8-A: 1- 4-Ben~loxy)-3-fluorophenyll-2-f4-(3,4-dihydro-1H isochromen-
7-yl)-4-hydroxypiperidin-1-yllethanone
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)-2-fluorophenyl]-2-bromoethanone and 4-(3,4-
dihydro-1H isochromen-7-yl)piperidin-4-ol: 792 mg (quant.) as a yellow solid
1H NMR (270 MHz, DMSO-d6) S = 7.54-6.94 (m, 11H), 5.22 (s, 2H), 4.72 (br.s,
1H), 4.66 (s, 2H), 3.85 (t, J--5.6 Hz, 2H), 3.68 (s, 2H), 2.73 (t, J--5.6 Hz,
2H), 2.70-
2.40 (m, 4H), 1.94-1.49 (m, 4H) ppm.
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54
MS (ESA; (M+H)+ = 476.18
8-B: 1-(2-f4-(Benz loxX)-3-fluorophenyll-2-h drox~ethyl}-4-(3,4-
dihydro-1H isochromen-7-yl)piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)-3-fluorophenyl]-2-[4-(3,4-dihydro-1H-
isochromen-7-yl)-4-hydroxypiperidin-1-yl]ethanone: 514 mg (66%) as a yellow
solid
1H NMR (270MHz, DMSO-d6) 8 = 7.48-7.30 (m, 6H), 7.24 (dd, J--7.9, 1.2 Hz, 1H),
7.12 (br.s, 1H), 7.06 (d, J--7.9 Hz, 1H), 6.88-6.80 (m ,2H), 5.11 (s, 2H),
5.01 (br.s,
1H), 4.93 (br.s, 1H), 4.68 (s, 1H), 4.66 (s, 2H), 3.86 (t, J--5.6 Hz, 2H),
2.73 (t, J--5.6
Hz, 2H), 2.70-2.39 (m, 6H), 1.96-1.81 (m, 2H), 1.60-1.48 (m, 2H) ppm.
MS (ESn; (M+H)+ = 478.20
8-C: 4-(3,4-Dihydro-1H isochromen-7-yl)-1-f2-(3-fluoro-4-
~droxy~hen l~ydrox~yllpiperidin-4-of
By the procedures of example 1, 1-{2-[4-(benzyloxy)-3-fluorophenyl]-2-
hydroxyethyl}-4-(3,4-dihydro-1H isochromen-7-yl)piperidin-4-of was converted
to
the title compound obtained as a white solid in 45% (190 mg) after
recrystallization
from 2-propanol.
1H NMR (270MHz, DMSO-d6) S = 9.71 (br.s, 1H), 7.31-7.20 (m, 2H), 7.12 (s, 1H),
7.06 (d, J--8.0 Hz, 1H), 6.59 (dd, J--8.4, 2.3 Hz, 1H), 6.48 (dd, J--12.3, 2.3
Hz, 1H),
4.95-4.85 (m, 1H), 4.70 (s, 1H), 4.66 (s, 2H), 3.86 (t, J--5.8 Hz, 2H), 2.76-
2.68 (m,
4H), 2.59-2.43 (m, 4H), 1.92-1.49 (m, 4H) ppm.
MS (ESn; (M+H)+ = 388.11, (M-H)- = 386.13
m.p. 186.1 °C
Example 9
1-f 2-(2-Fluoro-4-hvdroxvnhenvl)-2-hvdroxvethvll-4-(6-methoxvnvridin-3-
yl)piperidin-4-of
9-A: 1- ( 2-f 4-(Benzyloxy)-2-fluoro~henyll-2-hydroxyethyl ~ -4-(6-
methoxypyridin-3-~piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)-2-fluorophenyl]-2-bromoethanone and 4-(6-
methoxypyridin-3-yl)piperidin-4-of dihydrochloride: 386 mg (43%) as a yellow
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solid
1H NMR (270 MHz, DMSO-d6) $ = 8.23 (d, J--2.3 Hz, 1H), 7.80-7.73 (m, 1H),
7.50-7.34 (m, 6H), 6.90-6.80 (m, 2H), 6.75 (d, J--8.6 Hz, 1H), 5.11 (s, 2H),
4.98-
4.92 (m, 1H), 4.86 (s, 1H), 3.82 (s, 3H), 2.77-2.40 (m, 6H), 1.97-1.55 (m, 4H)
ppm.
5 MS (ESn; (M+H)+ = 453.19
9-B: 1-f2-(2-Fluoro-4-hydroxyphen l~ydroxyethyll-4-(6-
methoxypyridin-3-~piperidin-4-of
By the procedures of example 1, 1- f 2-[4-(benzyloxy)-2-fluorophenyl]-2
hydroxyethyl}-4-(6-methoxypyridin-3-yl)piperidin-4-of was converted to the
title
10 compound obtained as a white amorphous in 39°Io (120 mg) after
crystallization
from 2-propanol-diisopropylether.
1H NMR (270 MHz, DMSO-d6) ~ = 9.74 (s, 1H), 8.22 (br.s, 1H), 7.76 (dd, J--8.7,
1.8 Hz, 1H), 7.28 (t, J--8.6 Hz, 1H), 6.76 (d, J--8.7 Hz, 1H), 6.60 (d, J--8.6
Hz, 1H),
6.49 (d, J--12.0 Hz, 1H), 4.92 (br.s, 3H), 3.82 (s, 3H), 2.77-2.24 (m, 6H),
2.02-1.85
15 (m, 2H), 1.70-1.56 (m, 2H) ppm.
MS (ESA; (M+H)+ = 363.08, (M-H)- = 361.13
Example 10
4-(3-Fluorophenyl)-1-f2-hydroxy-2-(4-hydroxyphenyl)ethyll~peridin-4-of
10-A: 1-f 4-(Benzyloxy~phenyll-2-f 4-(3-fluorophenyl)-4-hydroxypiperidin-
20 1-yllethanone
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)phenyl]-2-bromoethanone (Indian J. Cl2em. Sect.
B,
1979, 17, 305) and 4-(3-fluorophenyl)piperidin-4-ol: 982 mg (quant.) as a
brown
solid
25 1H NMR (300 MHz, DMSO-d6) S = 8.02 (d, J--8.8 Hz, 2H), 7.48-7.17 (m, 8H),
7.12
(d, J--8.8 Hz, 2H), 7.06-6.98 (m, 1H), 5.22 (s, 2H), 4.98 (s, 1H), 3.79 (s,
2H), 2.76-
2.57 (m, 4H), 2.00-1.86 (m, 2H), 1.60-1.54 (m, 2H) ppm.
MS (ESA; (M+H)+ = 420.11
10-B: 1-( 2-f4-(Benzylox~~henyll-2-hydroxyethyl ~-4-(3-
30 fluorophenyl)piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)phenyl]-2-[4-(3-fluorophenyl)-4-
hydroxypiperidin-
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56
1-yl]ethanone: 653 mg (77%) as a yellow solid.
1H NMR (270 MHz, DMSO-d6) 8 = 7.48-7.20 (m, 10H), 7.08-6.92 (m, 3H), 5.09 (s,
2H), 4.91 (s, 1H), 4.82 (s, 1H), 4.70-4.62 (m, 1H), 2.75-2.36 (m, 6H), 1.96-
1.87 (m,
2H), 1.58-1.53 (m, 2H) ppm.
MS (ESn; (M+H)+ = 422.15
10-C: 4-(3-Fluorophenyl)-1-f2-hydrox~2-(4-
hydroxyphenyl)ethyllpiperidin-4-of
By the procedures of example 1, 1-{2-[4-(benzyloxy)phenyl]-2-
hydroxyethyl}-4-(3-fluorophenyl)piperidin-4-of was converted to the title
compound
obtained as a white solid in 49% (251 mg) after recrystallization from 2-
propanol.
1H NMR (300 MHz, DMSO-d6) 8 = 9.22 (s, 1H), 7.40-7.24 (m, 3H), 7.14 (d, J--8.4
Hz, 2H), 7.06-6.88 (m, 1H), 6.70 (d, J--8.4 Hz, 2H), 4.92 (s, 1H), 4.72 (s,
1H), 4.61
(br.s, 1H), 2.80-2.34 (m, 6H), 2.02-1.85 (m, 2H), 1.60-1.50 (m, 2H) ppm.
MS (ESA; (M+H)+ = 332.07, (M-H)- = 330.17
m.p.154.2°C
IR (KBr); 3325, 1616 cm 1
Example 11
1-f2-h dery-2-(4-hydroxyphenyl)ethyll-4-(6-methoxypyridin-3-~piperidin-4-of
11-A: 1-f4-(Benz~~phenyll-2-f4-h dery-4-(6-methoxypyridin-3-
yl)piperidin-1-yllethanone
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)phenyl]-2-bromoethanone and 4-(6-
methoxypyridin-3-yl)piperidin-4-of dihydrochloride: 789 mg (91 %) as a brown
solid
1H NMR (300 MHz, DMSO-d6) S = 8.24 (d, J--2.4 Hz, 1H), 8.01 (d, J 8.4 Hz, 2H),
7.77 (dd, ,l--8.6, 2.4 Hz, 1H), 7.49-7.32 (m, 5H), 7.12 (d, J--8.4 Hz, 2H),
6.75 (d,
J--8.6 Hz, 1H), 5.21 (br.s, 3H), 3.82 (s, 3H), 3.77 (s, ZH), 2.72-2.50 (m,
4H), 1.98-
1.86 (m, 2H), 1.63-1.59 (m, 2H) ppm.
MS (ESI]; (M+H)+ = 433.16
11-B: 1-(2-f4-(Benzylox~phenyll-2-hydrox~yll-4-(6-methoxyp irk
3-yl)-~iperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)phenyl]-2-[4-hydroxy-4-(6-methoxypyridin-3-
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yl)piperidin-1-yl]ethanone: 515 mg (59°Io) as a yellow solid
1H NMR (270 MHz, DMS O-d6) 8 = 8.23 (d, J--2.5 Hz, 1 H), 7.77 (dd, J--8.7, 2.5
Hz,
1H), 7.48-7.30 (m, 5H), 7.27 (d, J--8.6 Hz, 2H), 6.95 (d, J--8.6 Hz, 2H), 6.75
(d,
J 8.7 Hz, 1H), 5.09 (br.s, 2H), 4.86 (s, 2H), 4.70-4.63 (m, 1H), 3.83 (s, 3H),
2.74-
2.36 (m, 6H), 2.02-1.82 (m, 2H), 1.66-1.56 (m, 2H) ppm.
MS (E51]; (M+H)+ = 435.16
11-C: 1-d2-f4-(Benzyloxy)phenyll-2-h d~~yl~-4-(6-methox~yridin-
3-yl)-pi~eridin-4-of
By the procedures of example l, 1-{2-[4-(benzyloxy)phenyl]-2-
hydroxyethyl }-4-(6-methoxypyridin-3-yl)piperidin-4-of was converted to the
title
compound obtained as a white solid in 61 °7o (246 mg) after
recrystallization from 2-
propanol.
1H NMR (300 MHz, DMSO-d6) 8 = 9.22 (s, 1H), 8.23 (d, J--2.2 Hz, 1H), 7.77 (dd,
J--8.6, 2.2 Hz, 1H), 7.13 (d, J--8.0 Hz, 2H), 6.75 (d, J--8.6 Hz, 1H), 6.69
(d, J--8.0
Hz, 2H), 4.86 (s, 1H), 4.73 (s, 1H), 4.61 (br.s, 1H), 3.82 (s, 3H), 2.68-2.34
(m, 6H),
1.96-1.86 (m, 2H), 1.65-1.55 (m, 2H) ppm.
MS (E51); (M+H)+ = 345.08, (M-H)- = 343.15
m.p. 198.8°C
IR (I~Br); 3471, 3385, 1609 cm 1
Example 12
1-f2-Hydroxy-2-(4-h d~yphen l~yll-4-f4-(methoxymeth~phen~piperidin-4-
of
12-A: 4-f4-(Methoxymethyl)phenyllpiperidin-4-of
To a stirred solution of 1-bromo-4-(methoxymethyl)benzene (J. Med. Chem.
1998, 41, 940) (3.4 g, 20 mmol) in tetrahydrofuran (60 mL), n-butyllithium
(1.56 M
in hexane, 13.5 mL, 21 mmol) was added at -78 °C and the mixture was
stirred for 1
hour. Then to the mixture, a solution of ethyl 4-oxopiperidine-1-carboxylate
in
tetrahydrofuran was added at -78 °C and the mixture was stirred at room
temperature for 16 hours. The mixture was treated with sat. aq. ammonium
chloride
and extracted with dichloromethane. The extract was dried and evaporated. The
residue was dissolved with ethanol (10 mL). To the solution, potassium
hydroxide
(5.6 g, 100 mmol) was added and the mixture was refluxed for 2 hours. The
mixture
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was diluted with water and extracted with dichloromethane. The combined
organic
layer was dried and evaporated. The residue was purified by chromatography on
amine-silica gel, eluting with methyl alcohol / dichloromethane (1:8 v/v), to
afford
the titled compound as a yellow oil (450 mg).
1H NMR (270 MHz, CDC13) ~ = 7.50 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz,
2H),
4.45 (s, 2H), 3.40 (s, 3H), 3.19-2.97 (m, 4H), 2.10-1.96 (m, 2H), 1.78-1.70
(m, 2H)
ppm.
12-B : 1-f 4-(B enz~y)phenyll-2- ~ 4-hydroxy-4-f 4-
(methox~~phen~piperidin-1-yl lethanone
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)phenyl]-2-bromoethanone and 4-[4-
(methoxymethyl)phenyl]piperidin-4-ol: 954 mg (quant.) as a yellow solid.
1H NMR (300 MHz, DMSO-d6) b = 8.02 (d, J--8.8 Hz, 2H), 7.50-7.30 (m, 7H), 7.25
(d, J=8.1 Hz, 2H), 7.13 (d, J--8.8 Hz, 2H), 5.20 (s, 2H), 4.84 (s, 1 H), 4.37
(s, 2H),
3.81 (s, 2H), 3.26 (s, 3H), 3.03-2.59 (m, 4H), 2.02-1.88 (m, 2H), 1.61-1.56
(m, 2H)
ppm.
MS (ESn; (M+H)+ = 446.18
12-C: 1-12-f4-(Benzyloxy)phen 1~ d~~yll-4-f4-
(methoxymethyl)phenyll piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 1-[4-(benzyloxy)phenyl]-2-{4-hydroxy-4-[4-
(methoxymethyl)phenyl]piperidin-1-yl}ethanone: 597 mg (67%) as a yellow solid.
1H NMR (300 MHz, DMSO-d6) 8 = 7.48-7.22 (m, 11H), 6.96 (d, J--8.6 Hz, 2H),
5.09 (s, 2H), 4.84 (s, 1H), 4.77 (s, 1H), 4.68-4.66 (m, 1H), 4.37 (s, 2H),
3.27 (s, 3H),
2.78-2.36 (m, 6H), 2.02-1.85 (m, 2H), 1.62-1.50 (m, 2H) ppm.
MS (ESI); (M+H)+ = 448.18
12-D: 1-f 2-Hydroxy-2-(4-hydroxyphenyl)ethyll-4-[4-
(methoxymeth~phen~piperidin-4-of
By the procedures of example l, 1-{2-[4-(benzyloxy)phenyl]-2-
hydroxyethyl}-4-[4-(methoxymethyl)phenyl]piperidin-4-of was converted to the
title
compound obtained as a white solid in 65% (307 mg) after recrystallization
from 2-
propanol.
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1H NMR (270 MHz, DMSO-d6) 8 = 9.22 (s, 1H), 7.45 (d, J--8.2 Hz, 2H), 7.25 (d,
J--8.2 Hz, 2H), 7.14 (d, J--8.3 Hz, 2H), 6.70 (d, J--8.3 Hz, 2H), 4.77 (br.s,
2H), 4.65-
4.58 (m, 1H), 4.37 (s, 2H), 3.27 (s, 3H), 2.72-2.37 (m, 6H), 2.00-1.86 (m,
2H), 1.62-
1.52 (m, 2H) ppm.
MS (ESI]; (M+H)+ = 358.10, (M-H)- = 356.20
m.p. 169.6°C
IR (KBr); 3441, 3251, 1612 cm 1
Example 13
1-f2-H day-2-(4-h day-3-methylphen l~yll-4-f4-(methoxymeth~phen~
piperidin-4-of
13-A: 1-~ 3-Methyl-4-~(triisopropylsilyl)oxylphenyl ~ ethanone
The title compound was prepared according to the procedure described in
Example 2 from 1-(4-hydroxy-3-methylphenyl)ethanone: 9.64 g (94%) as a
colorless
oil.
1H NMR (270 MHz, CDC13) b = 7.78 (d, ,l--2.3 Hz, 1H), 7.70 (d, ,1--8.4, 2.3
Hz, 1H),
6.80 (d, J--8.4 Hz, 1H), 2.54 (s, 3H), 2.27 (s, 3H), 1.39-1.25 (m, 3H), 1.12
(d, J--7.3
Hz, 18H) ppm.
MS (E~; M+ = 306
13-B: 2-Bromo-1-~ 3-methyl-4-f (triisopropylsilyl)ox~phenyl lethanone
The title compound was prepared according to the procedure described in
Example 4 from 1-{3-methyl-4-[(triisopropylsilyl)oxy]phenyl}ethanone: 4.43 g
(71%) as a colorless oil.
1H NMR (300 MHz, CDC13) 8 = 7.81 (d, J--2.4 Hz, 1H), 7.74 (dd, J--8.6, 2.4 Hz,
1H), 6.82 (d, J--8.6 Hz, 1H), 4.01 (s, 2H), 2.28 (s, 3H), 1.38-1.26 (m, 3H),
1.12 (d,
J--7.1 Hz, 18H) ppm.
MS (En; M+ = 384, 386
13-C: 2- ( 4-Hydroxy-4-f 4-(methox ~rmethyl)phenyll piperidin-1-yl ~ -1- ~ 3-
methyl-4-f (triisopropylsilyl)oxylphenyl ~ ethanone
The title compound was prepared according to the procedure described in
Example 1 from 2-bromo-1-{3-methyl-4-[(triisopropylsilyl)oxy]phenyl}ethanone
and 4-[4-(methoxymethyl)phenyl]piperidin-4-ol: 1.13 g (quant.) as a yellow
solid.
1H NMR (270 MHz, DMSO-d6) 8 = 7.87-7.80 (m, 2H), 7.45 (d, J--8.0 Hz, 2H), 7.25
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(d, J--8.0 Hz, 2H), 6.88 (d, J--8.4 Hz, 1H), 4.83 (s, 1H), 4.38 (s, 2H), 3.81
(s, 2H),
3.27 (s, 3H), 2.71-2.55 (m, 4H), 2.24 (s, 3H), 2.02-1.90 (m, 2H), 1.65-1.55
(m, 2H),
1.42-1.12 (m, 3H), 1.09 (d, J--7.3 Hz, 18H) ppm.
MS (ESn; (M+H)+ = 526.28
5 13-D: 1-(2-H day-2-(3-methyl-4-[(triiso~p~yl)oxylphen 1y ~ethyl)-
4-[4-(methox~yl)phenyll~peridin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 2-{4-hydroxy-4-[4-(methoxymethyl)phenyl]piperidin-1-yl}-1-{3-
methyl-4-[(triisopropylsilyl)oxy]phenyl}ethanone: 1.1 g (quant.) as a yellow
oil.
10 1H NMR (270 MHz, DMSO-d6) ~ = 7.45 (d, J--8.3 Hz, 2H), 7.25 (d, J--8.3 Hz,
2H),
7.12 (s, 1H), 7.05 (d, J--8.4 Hz, 1H), 6.72 (d, J--8.4 Hz, 1H), 4.76 (s, 1H),
4.62 (br.s,
1H), 4.37 (br.s, 3H), 3.27 (s, 3H), 2.69-2.41 (m, 6H), 2.18 (s, 3H), 1.97-1.50
(m,
4H), 1.34-1.23 (m, 3H), 1.07 (d, J--7.1 Hz, 18H) ppm.
MS (ESn; (M+H)+ = 528.29
15 13-E: 1-f2-Hydroxy-2-(4-h droxy-3-methylphenyl)ethyll-4-f4-
(methoxymethyl)-phenyllpiperidin-4-of
By the procedures of example 2, 1-(2-hydroxy-2-{3-methyl-4-
[(triisopropylsilyl)oxy]phenyl }ethyl)-4-[4-(methoxymethyl)phenyl]piperidin-4-
of
was converted to the title compound obtained as a white solid in 69°10
(510 mg) after
20 recrystallization from 2-propanol.
1H NMR (270 MHz, DMSO-d6) b = 9.09 (s, 1H), 7.46 (d, J--8.1 Hz, 2H), 7.25 (d,
J--8.1 Hz, 2H), 7.03 (s, 1 H), 6.95 (d, J--8.1 Hz, 1 H), 6.70 (d, J--8.1 Hz, 1
H), 4.76 (s,
1H), 4.66 (s, 1H), 4.58 (br.s, 1H), 4.37 (s, 2H), 3.27 (s, 3H), 2.72-2.32 (m,
6H), 2.10
(s, 3H), 2.04-1.85 (m, 2H), 1.62-1.52 (m, 2H) ppm.
25 MS (ESI]; (M+H)+ = 372.12, (M-H)- = 370.19
m.p. 164.4°C
IR (KBr); 3472, 3163, 1611 cm 1
Example 14
1-[2-Hydroxy-2-(4-h day-3-meth~phenyl)ethyll-4-(5-methyl-1,3-thiazol-2-
30 ~piperidin-4-of
14-A: Ethyl 4-(5-Methyl-1,3-thiazol-2- 1~ dyroxypiperidine-1-
carboxylate
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The title com ound is re ared from 5-meth lthiazole 14.2
p p p y ( g) inseared of 7-
bromoisochroman according to the method described in Example 2 part A as oil
(13.8 g).
1H NMR (270 MHz, CDC13) & = 7.33 (d, J = 1.2 Hz, 1H), 4.15 (d, J = 7.1 Hz,
2H),
4.10-3.98 (m, 2H), 3.33 (t, J--11.3 Hz, 2H), 2.46 (d, J--1.2, 3H), 2.05 (dt,
J=4.8, 13.7
Hz, 2H), 1.90-1.80 (m, 2H), 1.27 (t, J--7.1, 3H) ppm.
14-B: 4-(5-Methyl-1,3-thiazol-2-yl)piperidine-4-of
The title compound is prepared from Ethyl 4-(5-Methyl-1,3-thiazol-2-yl)-4-
hydroxypiperidine-1-carboxylate (1.0 g) inseared of ethyl 4-(3,4-dihydro-1H
isochromen-7-yl)-4-hydroxypiperidine-1-carboxylate according to the method
described in Example 2 part B as oil (0.67 g).
1H NMR (300 MHz, CDC13) 8 = 7.34 (q, J = 1 Hz, 1H), 3.15-2.94 (m, 4H), 2.45
(d,
J =1 Hz, 3H), 2.12-2.01 (m, 2H), 1.95 (br, 1H), 1.89-1.80 (m, 2H). ppm.
14-C: 2-f4-H day-4-(5-methyl-1,3-thiazol-2-yl)piperidin-1-yll-1-~3-
methyl-4-f(triisopropylsil l~~phenyl}ethanone
The title compound was prepared according to the procedure described in
Example 1 from 2-bromo-1-{3-methyl-4-[(triisopropylsilyl)oxyphenyl}ethanone
and
4-(5-methyl-1,3-thiazol-2-yl)piperidin-4-ol: 1.12 g (quant.) as a yellow oil.
1H NMR (270 MHz, DMSO-d6) 8 = 7.84-7.81 (m, 2H), 7.35 (s, 1H), 6.87 (d, J--7.1
Hz, 1H), 5.77 (s, 1H), 3.75 (s, 2H), 2.76-2.40 (m, 4H), 2.39 (s, 3H), 2.23 (s,
3H),
2.16-1.99 (m, 2H), 1.72-1.62 (m, 2H), 1.40-1.14 (m, 3H), 1.08 (d, J--7.4 Hz,
18H)
ppm.
MS (ESn; (M+H)+ = 503.22
14-D: 1-(2-Hydroxy-2-(3-methyl-4-((triisoprop~yl)oxylphen l
4-L-methyl-1,3-thiazol-2-yl)piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 2-2-[4-hydroxy-4-(5-methyl-1,3-thiazol-2-yl)piperidin-1-yl]-1-
{3-
methyl-4-[(triisopropylsilyl)oxy]phenyl}ethanone: 1.01 g (quant.) as a yellow
oil.
IH NMR (300 MHz, DMSO-d6) 8 = 7.35 (d, J--1.3 Hz, 1H), 7.11 (d, J--2.4 Hz,
1H),
7.03 (dd, J--8.2, 2.4 Hz, 1H), 6.71 (d, J--8.2 Hz, 1H), 5.73 (s, 1H), 4.78 (s,
1H), 4.59
(br.s, 1H), 2.80-2.02 (m, 8H), 2.39 (d, J--1.3 Hz, 3H), 2.17 (s, 3H), 1.67-
1.62 (m,
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2H), 1.34-1.21 (m, 3H), 1.07 (d, J--7.3 Hz, 18H) ppm.
MS (ESn; (M+H)+ = 505.22
14-E: 1-f2-Hydroxy-2-(4-h droxy-3-methylphenyl)ethyll-4-(5-meth-1,3-
thiazol-2-yl)piperidin-4-of
By the procedures of example 2, 1-(2-hydroxy-2-{ 3-methyl-4-
[(triisopropylsilyl)oxy]phenyl } ethyl)-4-(5-methyl-1,3-thiazol-2-yl)piperidin-
4-of
was converted to the title compound obtained as a white solid in 57% (394 mg)
after
recrystallization from 2-propanol.
1H NMR (270 MHz, DMSO-d6) b = 8.97 (s, 1H), 7.23 (s, 1H), 6.90 (s, 1H), 6.82
(d,
J--8.1 Hz, 1H), 6.57 (d, J--8.1 Hz, 1H), 5.61 (s, 1H), 4.54 (s, 1H), 4.48-4.40
(m, 1H),
2.64-2.16 (m, 6H), 2.27 (s, 3H), 2.00-1.84 (m, 2H), 1.98 (s, 3H), 1.58-1.49
(m, 2H)
ppm.
MS (ESn; (M+H)+ = 349.05
m.p. 163.7 °C
IR (KBr); 3254, 1612 cm 1
Example 15
1-f2-Hydroxy-2-(4-hydroxy-3-methylphen l~yll-4-(3-methoxyphenyl)-pi erp idin-
4-0l hydrochloride
15-A: 2=f4-Hydroxy-4-(3-methoxyphen~piperidin-1-yll-1-~ 3-methyl-4-
~(triisoprop~ l~~phenyllethanone
The title compound was prepared according to the procedure described in
Example 1 from 2-bromo-1-{3-methyl-4-[(triisopropylsilyl)oxyphenyl]ethanone
and
4 4-(3-methoxyphenyl)piperidin-4-of (US 5668151): 1.06 g (quant.) as a yellow
oil.
1H NMR (300 MHz, DMSO-ds) b = 7.85-7.75 (m, 2H), 7.25-7.17 (m, 1H), 7.05-
7.01 (m, 2H), 6.88 (d, J--8.3 Hz, 1H), 6.79-6.75 (m, 1H), 4.81 (s, 1H), 3.77-
3.72 (m,
5H), 2.73-2.55 (m, 4H), 2.24 (s, 3H), 1.98-1.89 (m, 2H), 1.59-1.54 (m, 2H),
1.40-
1.21 (m, 3H), 1.08 (d, J--7.3 Hz, 18H) ppm.
MS (ESn; (M+H)+ = 512.28
15-B: 1-(2-H day-2-~3-methyl-4-f(triisopropylsil l~oxy~phenyl~ethyl)-
4-(3-methoxyphenyl)piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 2-[4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl]-1-{3-methyl-4-
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63
[(triisopropylsilyl)oxy]phenyl}ethanone): 1.01 g (quant.) as a yellow solid.
1H NMR (270 MHz, DMSO-d6) ~ = 7.26-6.70 (m, 7H), 4.76 (s, 1H), 4.64-4.58 (m,
1H), 3.75 (s, 3H), 2.73-2.34 (m, 6H), 2.18 (s, 3H), 1.99-1.87 (m, 2H), 1.57-
1.51 (m,
2H), 1.35-1.23 (m, 3H), 1.07 (d, J--7.1 Hz, 18H) ppm.
MS (ESA; (M+H)+ = 514.30
15-C: 1-f 2-Hydroxy-2-(4-hydroxy-3-meth~phenyl)ethyll-4-(3-
methoxyphenY)-piperidin-4-of
The title compound was prepared according to the procedure described in
Example 2 from 1-(2-hydroxy-2-{3-methyl-4-
[(triisopropylsilyl)oxy]phenyl}ethyl)
4-(3-methoxyphenyl)piperidin-4-ol: 433 mg (61 %) as a white solid.
1H NMR (270 MHz, DMSO-d6) 8 = 9.08 (s, 1H), 7.22 (t, J--8.1 Hz, 1H), 7.05-6.93
(m, 4H), 6.78-6.74 (m, 1H), 6.70 (t, J--8.1 Hz, 1H), 4.76 (s, 1H), 4.66 (s,
1H), 4.60-
4.55 (m, 1H), 3.75 (s, 3H), 2.73-2.34 (m, 6H), 2.10 (s, 3H), 2.00-1.86 (m,
2H), 1.60-
1.50 (m, 2H) ppm.
MS (ESI); (M+H)+ = 358.13, (M-H)- = 356.17
15-D: 1-f2-H dery-2-(4-h day-3-methylphenyl)ethyll-4-(3-methoxyphen~
piperidin-4-of hydrochloride
By the procedures of example 1, 1-[2-hydroxy-2-(4-hydroxy-3
methylphenyl)ethyl]-4-(3-methoxyphenyl)piperidin-4-of was converted to the
title
compound obtained as a white amorphous in 97% (456 mg) after crystallization
from 2-propanol-diisopropylether.
1H NMR (300 MHz, DMSO-d6) ~ = 9.69 (s, 1H), 9.37 (s, 1H), 7.29 (t, J--8.1 Hz,
1H), 7.12 (s, 1H), 7.08-7.02 (m, 3H), 6.84 (dd, J--8.1, 2.4 Hz, 1H), 6.78 (t,
J--8.1 Hz,
1H), 6.01 (s, 1H), 5.45 (s, 1H), 4.98 (br.s, 1H), 3.76 (s, 3H), 3.64-3.20 (m,
6H),
2.49-2.33 (m, 2H), 2.13 (s, 3H), 1.84-1.70 (m, 2H) ppm.
MS (ESA; (M+H)+ = 358.16, (M-H)- = 356.23
IR (KBr); 3226, 1610 cm 1
Example 16
4-(3-Fluorophenyl)-1-f2-hydroxy-2-(4-h dy roxy-2,5-dimeth~phenyl)ethyll-
piperidin-4-of
16-A: 2-Chloro-1-(4-h~xy-2,5-dimetl~lphenyl)ethanone
To a stirred suspension of alminium trichloride (32.5 g, 244 mmol) in carbon
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64
disulfide (200 mL) was added chloroacetyl chloride (7.26 mL, 90.0 mmol) at
room
remperature, and the mixture was stirred for 15 minutes. To the mixture, a
solution
of 2,5-dimethylphenol (10 g, 81.8 mmol) in carbon disulfide (50 mL) was added
and
the mixture was stirred under reflux for 10 hours. The mixture was poured onto
ice-H20 and extracted with ethyl acetate. The combined organic layer was
washed
with aq. sodium hydrogen carbonate, dried and evaporated. The residue was
crystallized from hexane to afford the titled compound as an orange solid (14
g).
1H NMR (270 MHz, DMSO-d6) 8 = 10.20 (s, 1H), 7.70 (s, 1H), 6.69 (s, 1H), 4.98
(s,
2H), 2.37 (s, 3H), 2.13 (s, 3H) ppm.
MS (E1); M+=198
16-B: 2-Chloro-1-~ 2,5-dimethyl-4-f (triisopropylsilyl)oxylphenyl lethanone
The title compound was prepared according to the procedure described in
Example 2 from 2-chloro-1-(4-hydroxy-2,5-dimethylphenyl)ethanone: 7.9 g
(quant.)
as a yellow solid.
1H NMR (270 MHz, CDCl3) 8 = 7.50 (s, 1H), 6.65 (s, 1H), 4.63 (s, 2H), 2.50 (s,
3H),
2.24 (s, 3H), 1.40-1.24 (m, 3H), 1.12 (d, J--7.1 Hz, 18H) ppm.
MS (EI); M+=355
16-C: 1- ( 2,5-Dimethyl-4-f (triisopropylsilyl)oxy~phenyl }-2-f 4-(3-
fluorophenyl)-4-hydroxypiperidin-1-yllethanone
The title compound was prepared according to the procedure described in
Example 1 from 2-chloro-1-{ 2,5-dimethyl-4-
[(triisopropylsilyl)oxy]phenyl}ethanone and 4-(3-fluorophenyl)piperidin-4-ol:
1.08 g
(quant.) as a yellow solid.
1H NMR (270 MHz, DMSO-d6) ~ = 7.73 (s, 1H), 7.42-7.22 (m, 3H), 7.07-6.98 (m,
1H), 6.63 (s, 1H), 4.94 (s, 1H), 3.70 (s, 2H), 3.01-2.55 (m, 4H), 2.37 (s,
3H), 2.20 (s,
3H), 1.97-1.83 (m, 2H), 1.60-1.53 (m, 2H), 1.39-1.19 (m, 3H), 1.08 (d, J--7.2
Hz,
18H) ppm.
MS (ESI); (M+H)+ = 514.33
16-D: 1-(2-~2,5-Dimethyl-4-f(triisopropylsil l~~phen 1~1-2-
hydroxyethyl)-4-(3-fluorophen~piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 1-{2,5-dimethyl-4-[(triisopropylsilyl)oxy]phenyl}-2-[4-(3-
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fluorophenyl)-4-hydroxypiperidin-1-yl]ethanone: 0.98 g (95%) as a yellow
solid.
1H NMR (300 MHz, DMSO-d6) 8 = 7.40-7.25 (m, 3H), 7.20 (s, 1H), 7.06-6.99 (m,
1H), 6.52 (s, 1H), 4.92 (s, 1H), 4.85-4.82 (m, 1H), 4.72 (s, 1H), 2.90-2.30
(m, 6H),
2.21 (s, 3H), 2.14 (s, 3H), 2.04-1.85 (m, 2H), 1.60-1.50 (m, 2H), 1.34-1.20
(m, 3H),
5 1.07 (d, J--7.1 Hz, 18H) ppm.
MS (ESn; (M+H)+ = 516.31
16-E: 4-(3-Fluorophenyl)-1-f2-hydroxy-2-(4-hydrox -
dimeth~phen, 1y )eth.~piperidin-4-of
By the procedures of example 2, 1-(2-{2,5-dimethyl-4-
10 [(triisopropylsilyl)oxy]phenyl}-2-hydroxyethyl)-4-(3-fluorophenyl)piperidin-
4-of
was converted to the title compound obtained as a white solid in 55% (372 mg)
after
recrystallization from 2-propanol.
1H NMR (270 MHz, DMSO-d6) b = 8.95 (s, 1H), 7.41-7.25 (m, 3H), 7.10 (s, 1H),
7.06-6.99 (m, 1H), 6.51 (s, 1H), 4.92 (s, 1H), 4.85-4.77 (m, 1H), 4.60 (s,
1H), 2.81-
15 2.29 (m, 6H), 2.16 (s, 3H), 2.07 (s, 3H), 2.00-1.90 (m, 2H), 1.59-1.53 (m,
2H) ppm.
MS (ES>7; (M+H)+ = 360.16, (M-H)- = 358.22
m.p. 192.7°C
IR (KBr); 3197, 1616 cm I
Example 17
20 1-f2-Hydroxy-2-(4-hydroxy 2,5-dimethXlphen" l~yll-4-(6-methoxy~yridin-3-
yl)piperidin-4-of
17-A: 1-( 2,5-Dimethyl-4-~(triisopro~ylsil.1)oxylphenyll-2-f4-hydroxy-4-
(6-methoxypyridin-3-yl)piperidin-1-yll ethanone
The title compound was prepared according to the procedure described in
25 Example 1 from 2-chloro-1-{2,5-dimethyl-4-
[(triisopropylsilyl)oxy]phenyl}ethanone and 4-(6-methoxypyridin-3-yl)piperidin-
4-
ol dihydrochloride: 1.56 g (99%) as a black solid.
1H NMR (270 MHz, DMSO-d6) S = 8.23 (d, J--2.3 Hz, 1H), 7.76 (dd, J--8.6, 2.3
Hz,
1H), 7.73 (s, 1H), 6.75 (d, J--8.6 Hz, 1H), 6.63 (s, 1H), 4.89 (s, 1H), 3.82
(s, 3H),
30 3.71 (s, 2H), 2.72-2.45 (m, 4H), 2.37 (s, 3H), 2.20 (s, 3H), 1.98-1.86 (m,
2H), 1.
MS (ESA; (M+H)+ = 527.3663-1.58 (m, 2H), 1.39-1.27 (m, 3H), 1.08 (d, J--7.4
Hz,
18H) ppm.
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17-B: 1-(2-~ 2,5-Dimeth~l-4-~(triisoproRylsilyl)oxylphenyl ~-2-
h d~yethyl)-4-(6-methoxypyridin-3-yl)piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 1-{2,5-dimethyl-4-[(triisopropylsilyl)oxy]phenyl}-2-[4-hydroxy-
4-
(6-methoxypyridin-3-yl)piperidin-1-yl]ethanone: 1.38 g (87°70) as a
black solid.
1H NMR (300 MHz, DMSO-d6) 8 = 8.23 (d, J--2.6 Hz, 1H), 7.77 (dd, J--8.6, 2.6
Hz,
1H), 7.20 (s, 1H), 6.76 (d, J--8.6 Hz, 1H), 6.51 (s, 1H), 5.76 (s, 1H), 4.87-
4.70 (m,
2H), 3.83 (s, 3H), 2.77-2.28 (m, 6H), 2.20 (s, 3H), 2.14 (s, 3H), 1.99-1.87
(m, 2H),
1.63-1.58 (m, 2H), 1.33-1.17 (m, 3H), 1.07 (d, J--6.2 Hz, 18H) ppm.
MS (ESA; (M+H)+ = 529.34
17-C: 1-f2-Hydroxy-2-(4-h, day-2,5-dimeth~phenyl)ethyll-4-(6-
methoxypyridin-3-~)piperidin-4-of
By the procedures of example 2, 1-(2-{2,5-dimethyl-4-
[(triisopropylsilyl)oxy]phenyl }-2-hydroxyethyl)-4-(6-methoxypyridin-3-
yl)piperidin-
4-0l was converted to the title compound obtained as a white solid in 42% (407
mg)
after recrystallization from 2-propanol.
1H NMR (270 MHz, DMSO-d6) 8 = 8.94 (s, 1H), 8.24 (d, J--2.1 Hz, 1H), 7.78 (dd,
J--8.6, 2.1 Hz, 1H), 7.10 (s, 1H), 6.76 (d, J--8.6 Hz, 1H), 6.50 (s, 1H), 4.85
(s, 1H),
4.84-4.79 (m, 1H), 4.60 (s, 1H), 3.82 (s, 3H), 2.75-2.28 (m, 6H), 2.16 (s,
3H), 2.07
(s, 3H), 2.00-1.90 (m, 2H), 1.66-1.58 (m, 2H) ppm.
MS (ESn; (M+H)~ = 373.17, (M-H)- = 371.23
m.p. 156.5°C
IR (KBr); 3282, 3165, 1607 cm 1
Example 18
4-(6-Ethoxypyridin-3-yl)-1-f2-hydroxy-2-(4-hydroxy-3-methylphenyl)eth
~peridin-4-of
18-A: ter t-Butyl 4-(6-ethoxypyridin-3-yl)-4-hydroxypiperidine-1-
carbox,
To a stirred solution of 5-bromo-2-ethoxypyridine (Yakugaku Zasshi, 1952,
72, 381)(5.02 g, 24.8 mmol) in diethylether (90 mL) was added dropwise n-
butyllithium (1.56 M, 15.9 mL, 24.8 mmol) at -78 °C under nitrogen and
the
mixture was stirred for 50 minutes at -78 °C. To the mixture, a
solution of tert-
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67
butyl 4-oxopiperidine-1-carboxylate (4.49 g, 22.5 mmol) in diethylether (10
mL)
was added at -78 °C. The mixture was stirred at -78 °C for 2
hours and at room
temperature for 3 hours. The mixture was treated with H20 and extracted with
ethyl
acetate. The combined organic layer was dried and evaporated. The residue was
purified by chromatography on silica gel, eluting with triethylamine / ethyl
acetate /
hexane (0.05:1:2 v/v/v), to afford the titled compound as a yellow oil (3.50
g, 48 %).
1H NMR (300MHz, CDC13) b = 8.23 (dd, J = 2.6, 0.7 Hz, 1H), 7.68 (dd, J = 8.8,
2.6
Hz, 1H), 6.71 (dd, J = 8.8, 0.7 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.00 (br.s,
2H),
3.16-3.30 (m, 2H), 2.02-1.86 (m, 2H), 1.80-1.70 (m, 2H), 1.48 (s, 9H), 1.39
(t, J =
7.1 Hz, 3H) ppm.
MS (En; M+ =322
18-B: 4-(6-Ethoxypyridin-3-yl)piperidin-4-of dihydrochloride
Hydrogen chloride (10 mL, 40 mmol), 4.0 M solution in ethyl acetate, was
added to a solution of tert-butyl 4-(6-ethoxypyridin-3-yl)-4-hydroxypiperidine-
1
carboxylate (3.50 g, 10.9 mmol) in ethyl acetate (40 mL). The mixture was
stirred at
50 °C for 1 hour. The precipitate was collected by filtration to afford
the title
compound as a yellow solid (3.09 g, 96 %).
1H NMR (300MHz, DMSO) 8 = 9.34 (br.s, 1H), 9.21 (br.s, 1H), 8.23 (d, J = 2.6
Hz,
1H), 7.89 (dd, J= 8.8, 2.6 Hz, 1H), 6.97 (d, J= 8.8 Hz, 1H), 6.36 (br.s, 2H),
4.34 (q,
J = 7.0 Hz, 2H), 3.30-1.75 (m, 8H), 1.33 (t, J = 7.0 Hz, 3H) ppm.
MS (E1]; M+=295
18-C: 2-~4-(6-Ethoxypyridin-3-, l~ydroxypiperidin-1-yll-1-(3-meth
4-~(triisoproR~silyl)oxylt~henyl ~ ethanone
The title compound was prepared according to the procedure described in
Example 1 from 2-bromo-1-{3-methyl-4-[(triisopropylsilyl)oxyphenyl]-ethanone
and 4-(6-Ethoxypyridin-3-yl)piperidin-4-of dihydrochloride: 1.01 g (96%) as a
yellow solid.
1H NMR (300 MHz, DMSO-d6) S = 8.21 (d, J--2.6 Hz, 1H), 7.84-7.79 (m, 2H), 7.76
(dd, J--8.6, 2.6 Hz, 1H), 6.88 (d, J--8.4 Hz, 1H), 6.72 (d, J--8.6 Hz, 1H),
4.90 (s, 1H),
4.27 (q, J--7.0 Hz, 2H), 3.78 (s, 2H), 3.17-2.56 (m, 4H), 2.24 (s, 3H), 2.05-
1.58 (m,
4H), 1.40-1.27 (m, 6H), 1.08 (d, J--7.3 Hz, 18H) ppm.
MS (ESn; (M+H)+ = 527.32
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18-D: 4-(6-Ethoxyuyridin-3-yl)-1-(2-hydroxy-2- ~ 3-methyl-4-
((triisopropylsilyl)ox ~~1-phenyl~ethyl)~iperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 2-[4-(6-ethoxypyridin-3-yl)-4-hydroxypiperidin-1-yl]-1-{3-
methyl
4-[(triisopropylsilyl)oxy]phenyl}ethanone: 840 mg (79%) as a yellow solid.
1H NMR (300 MHz, DMSO-d6) 8 = 8.21 (d, J--2.6 Hz, 1H), 7.75 (d, J--8.6, 2.6
Hz,
1H), 7.13-7.02 (m, 2H), 6.80-6.68 (m, 2H), 4.84 (s, 1H), 4.78-4.76 (m, 1H),
4.62
(br.s, 1H), 4.27 (q, J--7.0 Hz, 2H), 2.75-2.28 (m, 6H), 2.18 (s, 3H), 2.00-
1.89 (m,
2H), 1.62-1.57 (m, 2H), 1.31 (q, J--7.0 Hz, 2H), 1.33-1.16 (m, 3H), 1.07 (d, J-
-7.1
Hz, 18H) ppm.
MS (ESA; (M+H)+ = 529.32
18-E: 4-(6-EthoxXpyridin-3 yl)-1-f2-hydroxy-2-(4-h,~y-3-
meth~t~henyl)ethyll-piperidin-4-of
By the procedures of example 2, 4-(6-ethoxypyridin-3-yl)-1-(2-hydroxy-2-
{3-methyl-4-[(triisopropylsilyl)oxy]phenyl}ethyl)piperidin-4-of was converted
to the
title compound obtained as a white solid in 51% (300 mg) after
recrystallization
from 2-propanol-diisopropylether.
1H NMR (270 MHz, DMSO-d6) 8 = 9.08 (s, 1H), 8.21 (d, J--2.5 Hz, 1H), 7.76 (d,
J--8.5, 2.5 Hz, 1H), 7.02 (d, J--1.8 Hz, 1H), 6.95 (dd, J--8.1, 1.8 Hz, 1H),
6.72 (d,
J--8.5 Hz, 1H), 6.69 (d, J--8.1 Hz, 1H), 4.83 (s, 1H), 4.65 (s, 1H), 4.55
(br.s, 1H),
4.27 (t, ,1--7.1 Hz, 3H), 2.78-2.32 (m, 6H), 2.10 (s, 3H), 2.00-1.82 (m, 2H),
1.62-1.57
(m, 2H), 1.30 (q, J--7.1 Hz, 2H) ppm.
MS (ESA; (M+H)+ = 373.17, (M-H)- = 371.23
m.p. 189.3°C
IR (KBr); 3300, 1611 cm 1
Example 19
1-~2-Hydrox -~ 2-(4-h, day-2,5-dimethylphen l~yll-4-f4-(methox~yl)-
phen~~peridin-4-of
19-A: 1-~ 2,5-Dimethyl-4-f (triisopropylsilyl)oxylphenyl ~-2-~ 4-hydroxy-4-
~4-(methox~yl)phen~piperidin-1-yl } ethanone
The title compound was prepared according to the procedure described in
Example 1 from 1-{2,5-dimethyl-4-[(triisopropylsilyl)oxy]phenyl}-2-{4-hydroxy-
4-
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[4-(methoxymethyl)phenyl]piperidin-1-yl}ethanone: 1.05 g (97%) as a yellow
solid.
1H NMR (270 MHz, DMSO-d6) 8 = 7.72 (s, 1H), 7.43 (d, J--8.2 Hz, 2H), 7.23 (d,
J--8.2 Hz, 2H), 6.62 (s, 1H), 4.77 (s, 1H), 4.35 (s, 2H), 3.67 (s, 2H), 3.25
(s, 3H),
2.70-2.31 (m, 4H), 2.35 (s, 3H), 2.18 (s, 3H), 1.97-1.91 (m, 2H), 1.59-1.47
(m, 2H),
1.40-1.20 (m, 3H), 1.06 (d, J--7.2 Hz, 18H) ppm.
MS (ESn; (M+H)+ = 540.33
19-B: 1-(2-~2,5-Dimethyl-4-f(triisopro~ylsil 1~)oxylphen 1y }=2-
h d~yethyl)-4-f4-(methoxymethyl)phenyllpiperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 1-{2,5-Dimethyl-4-[(triisopropylsilyl)oxy]phenyl}-2-{4-hydroxy-
4-
[4-(methoxymethyl)phenyl]piperidin-1-yl}ethanone: 994 mg (90%) as a yellow
solid.
1H NMR (300 MHz, DMSO-d6) 8 = 7.45 (d, J--8.1 Hz, 2H), 7.24 (d, ,1--8.1 Hz,
2H),
7.19 (s, 1H), 6.50 (s, 1H), 4.86-4.66 (m, 3H), 4.36 (s, 2H), 3.26 (s, 3H),
2.79-2.27
(m, 6H), 2.19 (s, 3H), 2.13 (s, 3H), 2.03-1.84 (m, 2H), 1.60-1.49 (m, 2H),
1.36-1.18
(m, 3H), 1.06 (d, J--6.4 Hz, 18H) ppm.
MS (ESA; (M+H)+ = 542.35
19-C: 1-~2-Hydroxy-2-(4-hydroxy-2,5-dimethylphenyl)ethpll-4-~4-
(methoxymethyl)-phenyllpiperidin-4-of
By the procedures of example 2, 1-(2-{2,5-dimethyl-4-
[(triisopropylsilyl)oxy]phenyl}-2-hydroxyethyl)-4-[4-
(methoxymethyl)phenyl]piperidin-4-of was converted to the title compound
obtained as a white solid in 60°70 (465 mg) after recrystallization
from 2-propanol.
1H NMR (270 MHz, DMSO-d6) 8 = 8.94 (s, 1H), 7.46 (d, J--8.2 Hz, 2H), 7.25 (d,
J--8.1 Hz, 2H), 7.10 (s, 1H), 6.50 (s, 1H), 4.81 (d, J--7.7 Hz, 1H), 4.75 (s,
1H), 4.59
(br.s, 1H), 4.37 (s, 2H), 3.27 (s, 3H), 2.80-2.27 (m, 6H), 2.16 (s, 3H), 2.07
(s, 3H),
2.01-1.88 (m, 2H), 1.59-1.54 (m, 2H) ppm.
MS (ESn; (M+H)+ = 386.18, (M-H)- = 384.23
m.p. 166.3°C
IR (KBr); 3343, 1620 crn 1
Example 20
1-f2-(3-Ethyl-4-h dy-roxyphenyl)-2-hydroxyethyll-4-(6-methoxypyridin-3-
yl)piperidin-4-of hydrochloride
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20-A: 2-Chloro-1-(3-ether-h droxyphenyl)ethanone
The title compound was prepared according to the procedure described in
Example 16 from 2-ethylphenol: 2.02 g (46%) as a white-red solid.
1H NMR (300 MHz, CDCl3) 8 = 7.81 (d, J--2.2 Hz, 1H), 7.74 (dd, J--8.4, 2.2 Hz,
5 1H), 6.85 (d, J--8.4 Hz, 1H), 5.87 (s, 1H), 4.67 (s, 2H), 2.69 (q, J--7.5
Hz, 2H), 1.26
(t, J--7.5 Hz, 3H) ppm.
MS (El]; M+=198
20-B: 2-Chloro-1-( 3-ethyl-4-f (triisoprop~yl)oxylphenyl lethanone
The title compound was prepared according to the procedure described in
10 Example 2 from 2-chloro-1-(3-ethyl-4-hydroxyphenyl)ethanone: 3.09 g (86%)
as a
yellow oil.
1H NMR (300 MHz, CDC13) S = 7.80 (d, J--2.4 Hz, 1H), 7.71 (dd, J--8.4, 2.4 Hz,
1H), 6.82 (d, J--8.4 Hz, 1H), 4.66 (s, 2H), 2.69 (q, J--7.5 Hz, 2H), 1.40-1.27
(m, 3H),
1.22 (t, J--7.5 Hz, 3H), 1.12 (d, J--7.1 Hz, 18H) ppm.
15 MS (El]; M+=354
20-C: 1-(2-(3-Ethyl-4-[(triisoprop~ l~~phenyll-2-hydroxyethyl)-4-
(6-methoxypyridin-3-~piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 2-chloro-1-{3-ethyl-4-[(triisopropylsilyl)oxy]phenyl}ethanone
and
20 4-(6-methoxypyridin-3-yl)piperidin-4-of dihydrochloride: 987 mg (93%) as a
yellow
oil.
1H NMR (270 MHz, DMSO-d6) 8 = 8.23 (d, J--2.5 Hz, 1H), 7.77 (dd, J--8.6, 2.5
Hz,
1H), 7.13 (d, J--2.0 Hz, 1H), 7.05 (dd, J--8.4, 2.0 Hz, 1H), 6.75 (d, J--8.6
Hz, 1H),
6.72 (d, J--8.4 Hz, 1H), 4.86 (s, 1H), 4.79 (s, 1H), 4.63 (br.s, 1H), 3.82 (s,
3H), 2.72-
25 2.34 (m, 8H), 2.02-1.76 (m, 2H), 1.62-1.57 (m, 2H), 1.36-1.11 (m, 6H), 1.07
(d,
J--7.3 Hz, 18H) ppm.
MS (ESn; (M+H)+ = 529.31
20-D: 1-[2-(3-Ethyl-4-hydroxyphen l~ydrox~yll-4-(6-
methoxypyridin-3- ~~l-piperidin-4-of
30 The title compound was prepared according to the procedure described in
Example 2 from 1-(2-{3-ethyl-4-[(triisopropylsilyl)oxy]phenyl}-2-hydroxyethyl)-
4-
(6-methoxypyridin-3-yl)piperidin-4-ol: 376 mg (50%) as a yellow oil.
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1H NMR (270 MHz, DMSO-d6) 8 = 9.08 (s, 1H), 8.23 (d, J-_2.6 Hz, 1H), 7.77 (dd,
J--8.7, 2.6 Hz, 1H), 7.03 (d, J--2.0 Hz, 1H), 6.96 (dd; J--8.3, 2.0 Hz, 1H),
6.76 (d,
J--8.7 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 4.87 (s, 1H), 4.69 (s, 1H), 4.61-4.56
(m, 1H),
3.83 (s, 3H), 2.78-2.33 (m, 8H), 2.02-1.86 (m, 2H), 1.63-1.57 (m, 2H), 1.12
(t, J=7.6
Hz, 3H) ppm.
20-E: 1-~2-(3-Ether d~yphen l~, d~yethyll-4-(6-
methoxypyridin-3-~piperidin-4-of hydrochloride
By the procedures of example 1, 1-[2-(3-ethyl-4-hydroxyphenyl)-2
hydroxyethyl]-4-(6-methoxypyridin-3-yl)piperidin-4-of was converted to the
title
compound obtained as a white amorphous in 97% (400 mg) after crystallization
from ethanol-hexane.
1H NMR (270 MHz, DMSO-d6) ~ = 9.65 (br.s, 1H), 9.32 (s, 1H), 8.26 (br.s, 1H),
7.78 (d, J--8.7 Hz, 1H), 7.12 (s, 1H), 7.05 (d, J--8.1 Hz, 1H), 6.84-6.76 (m,
2H), 5.92
(br.s, 1H), 5.49 (s, 1H), 4.96 (s, 1H), 3.84 (s, 3H), 3.65-1.77 (m, 12H), 1.14
(t, J--7.6
Hz, 3H) ppm.
MS (ESI); (M+H)+ = 373.12, (M-H)- = 371.21
IR (KBr); 3263, 1609 cm 1
Example 21
1-f2-(2-Fluoro-4-h day-5-methylphen 1~ d~yethyll-4-(6-methoxypyridin-3-
~piperidin-4-of
21-A: 1-(2-Fluoro-4-hydroxy-5-meth~phenyl)ethanone
The title compound was prepared according to the procedure described in
Example 16 from 5-fluoro-2-methylphenol (Tetrahedron, 1959, 6, 315): 856 mg
(43%) as a yellow oil.
1H NMR (270 MHz, CDC13) 8 = 7.71 (d, J--8.6 Hz, 1H), 6.57 (d, J--12.0 Hz, 1H),
5.99 (s, 1H), 2.59 (d, J--5.3 Hz, 3H), 2.23 (s, 3H) ppm.
MS (E1); M+=168
21-B: 1-~ 2-Fluoro-5-methyl-4-[(triisopropylsil l~ylphenyl ) ethanone
The title compound was prepared according to the procedure described in
Example 2 from 1-(2-fluoro-4-hydroxy-5-methylphenyl)ethanone: 1.39 g (85%) as
a
yellow oil.
1H NMR (270 MHz, CDC13) S = 7.70 (d, J--9.0 Hz, 1H), 6.50 (d, J--12.7 Hz, 1H),
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2.58 (d, J--5.3 Hz, 3H), 2.20 (s, 3H), 1.39-1.25 (m, 3H), 1.12 (d, J=7.1 Hz,
18H)
ppm.
MS (E~; M+=324
21-C: 2-Bromo-1-( 2-fluoro-5-meth-4-
[(triisoprop~yl)ox~phenyl}ethanone
The title compound was prepared according to the procedure described in
Example 4 from 1-{2-fluoro-5-methyl-4-[(triisopropylsilyl)oxy]phenyl}ethanone:
1.9 g (quant.) as a yellow oil.
1H NMR (270 MHz, CDC13) 8 = 7.76 (d, J--8.9 Hz, 1H), 6.52 (d, J--12.9 Hz, 1H),
4.47 (d, J--2.0 Hz, 2H), 2.21 (s, 3H), 1.39-1.23 (m, 3H), 1.12 (d, J--7.3 Hz,
18H)
ppm.
MS (En; M+=402, 404
21-D: 1-( 2-Fluoro-5-methyl-4-~(triisopropylsilyl)oxylphenyl )-2-f 4-
hydroxy-4-(6-methoxypyridin-3-yl)piperidin-1-yllethanone
The title compound was prepared according to the procedure described in
Example 1 from 2-bromo-1-{ 2-fluoro-5-methyl-4-
[(triisopropylsilyl)oxy]phenyl}ethanone and 4-(6-methoxypyridin-3-yl)piperidin-
4-
ol dihydrochloride: 1.05 g (99%) as a yellow oil.
1H NMR (270 MHz, DMSO-d6) 8 = 8.22 (d, J--2.6 Hz, 1H), 7.76 (dd, J--8.6, 2.6
Hz,
1H), 7.68 (d, J--8.6 Hz, 1H), 6.75 (d, J--8.6 Hz, 1H), 6.63 (d, J--12.5 Hz,
1H), 4.90
(s, 1H), 3.82 (s, 3H), 3.71 (s, 2H), 2.65-1.57 (m, 8H), 2.29 (s, 3H), 1.42-
1.31 (m,
3H), 1.08 (d, J--7.4 Hz, 18H) ppm.
MS (ESA; (M+H)+ = 531.28
21-E: 1-(2-( 2-Fluoro-5-methyl-4-[(triisopropylsilyl)oxylphenyl }-2-
h d~yethyl)-4-(6-methoxyp irk=yl)piperidin-4-of
The title compound was prepared according to the procedure described in
Example 1 from 1-{2-fluoro-5-methyl-4-[(triisopropylsilyl)oxy]phenyl}-2-[4-
hydroxy-4-(6-methoxypyridin-3-yl)piperidin-1-yl]ethanone: 354 mg
(33°70) as a
yellow oil.
1H NMR (270 MHz, DMSO-d6) 8 = 8.21 (br.s, 1H), 7.75 (d, J--8.6 Hz, 1H), 7.26
(d,
J--8.9 Hz, 1H), 6.75 (d, J--8.6 Hz, 1H), 6.48 (d, J--11.2 Hz, 1H), 4.92-4.83
(m, 3H),
3.82 (s, 3H), 2.67-1.56 (m, 10H), 2.15 (s, 3H), 1.34-1.25 (m, 3H), 1.07 (d, J--
7.4 Hz,
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18H) ppm.
MS (ESn; (M+H)+ = 533.29
21-F: 1-f2-(2-Fluoro-4-hydroxy-5-methylphenyl)-2-hydroxyethyll-4-(6-
methoxypyridin-3-~piperidin-4-of
By the procedures of example 2, 1-(2-{2-fluoro-5-methyl-4-
[(triisopropylsilyl)oxy]phenyl }-2-hydroxyethyl)-4-(6-methoxypyridin-3-
yl)piperidin-
4-0l was converted to the title compound obtained as a white amorphous in 100%
(260 mg) after crystallization from 2-propanol.
1H NMR (270 MHz, DMSO-d6) 8 = 9.59 (s, 1H), 8.22 (d, J--2.6 Hz, 1H), 7.76 (dd,
J 8.7, 2.6 Hz, 1H), 7.15 (d, J--8.7 Hz, 1H), 6.75 (d, J--8.7 Hz, 1H), 6.48 (d,
J--11.9
Hz, 1H), 4.92-4.83 (m, 3H), 3.82 (s, 3H), 2.72-2.36 (m, 6H), 2.07 (s, 3H),
1.95-1.56
(m, 4H) ppm.
MS (ESn; (M+H)+ = 377.13, (M-H)- = 375.20
m.p. 183.6°C
IR (KBr); 3260, 1614 cm 1
Example 22
1-f2-(2-Fluoro-4-h~droxy-5-meth~phen 1~ d~~yll-4-(3-fluorophenyl)-
piperidin-4-of
22-A: 2-Chloro-1-~ 2-fluoro-5-methyl-4-
f(triisoprop~yl)ox~phenyllethanone
The title compound was prepared according to the procedure described in
Example 16 from 5-fluoro-2-methylphenol: 2.7 g (27%) as a brown oil.
1H NMR (270 MHz, CDC13) 8 = 7.78 (d, J--8.7 Hz, 1H), 6.52 (d, J--13.0 Hz, 1H),
4.68 (d, J--2.9 Hz, 2H), 2.22 (s, 3H), 1.39-1.17 (m, 3H), 1.12 (d, J--7.3 Hz,
18H)
ppm.
MS (E~; M+=358
22-B: 1-~2-Fluoro-5-methyl-4-f(triisopropylsil, l~ylphenyll-2-f4-(3-
fluorophen 1~-4-hydroxypiperidin-1-yllethanone
The title compound was prepared according to the procedure described in
Example CJ-26562-27 from 2-chloro-1-{2-fluoro-5-methyl-4-
[(triisopropylsilyl)oxy]phenyl}ethanone: 144 mg (14%) as a brown solid.
1H NMR (270 MHz, DMSO-d6) 8 = 7.76-7.54 (m, 11-1), 7.40-7.17 (m, 3H), 7.07-
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6.94 (m, 1H), 6.68-6.54 (m, 1H), 4.93 (s, 1H), 3.72-3.60 (m, 2H), 2.71-1.81
(m, 6H),
2.17 (s, 3H), 1.59-1.48 (m, 2H), 1.45-1.24 (m, 3H), 1.07 (d, J--7.4 Hz, 18H)
ppm.
MS (ESI); (M+H)+ = 518.24
22-C: 1-[2-(2-Fluoro-4-hydroxy-5-methylphen l~h dy roxyethyll-4-(3-
fluorophenyl)piperidin-4-of
By the procedures of example 2, 1-{2-fluoro-5-methyl-4-
[(triisopropylsilyl)oxy]phenyl }-2-[4-(3-fluorophenyl)-4-hydroxypiperidin-1-
yl]ethanone was converted to the title compound obtained as a white solid in
76%
(77 mg) after crystallization from 2-propanol-diisopropylether.
1H NMR (300 MHz, DMSO-d6) ~ = 9.63 (br.s, 1H), 7.37-7.25 (m, 3H), 7.16 (d,
J=8.6 Hz, 1H), 7.06-7.01 (m, 1H), 6.56-6.48 (m, 1H), 4.93-4.89 (m, 3H), 2.75-
2.30
(m, 6H), 2.08 (s, 3H), 1.97-1.77 (m, 2H), 1.58-1.53 (m, 2H) ppm.
MS (ESI]; (M+H)+ = 364.11, (M-H)- = 362.17
m.p. 161.7°C
IR (KBr); 3377, 3202, 1622 cm I
Example 23
4-(6-Fluoro-5-methoxypyridin-2-yl)-1-f2-h day-2-(4-hydroxy-3-
meth~phenyl)ethyll~peridin-4-of
23-A: 6-Bromo-2-fluoro~yridin-3-of
To a stirred solution of 2-fluoropyridin-3-of (J. Labelled Courrzpound.
Radioplzann., 1998, 41, 451)(3.81 g, 33.7 mmol) and sodium acetate (2.76 g,
33.7
mmol) in acetic acid (30 mL) was added bromine (1.74 mL, 33.7 mmol) at 0
°C, and
the mixture was stirred at room temperature for 3.5 hours. The mixture was
poured
onto ice-aq.sodium hydroxide and extracted with ethyl acetate. The combined
organic layer was dried and evaporated to afford the titled compound as a
yellow
solid (4.67 g, 72 °Io).
1H NMR (270MHz, DMSO-d6) 8 = 7.29 (d, J = 8.2 Hz, 1H), 7.28 (s, 1H), 7.23 (d,
J
= 8.2 Hz, 1H) ppm.
MS (E~; M+=191, 193
23-B: 6-Bromo-2-fluoro-3-methoxyp riy 'dine
To a stirred solution of 6-bromo-2-fluoropyridin-3-of (4.67 g, 24.3 mmol) and
sodium methoxide (1.38 g, 25.5 mmol) in N,N dimethylformamide (50 mL) was
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added methyl iodide (1.59 mL, 25.5 mmol) at 0 °C, and the mixture was
stirred at
room temperature for 12 hours. The mixture was treated with HZO and extracted
with ethyl acetate. The combined organic layer was dried and evaporated. The
residue was purified by chromatography on silica gel, eluting with ethyl
acetate l
5 hexane (1:5 vlv), to afford the titled compound as a yellow oil (2.43 g, 49
%).
1H NMR (270MHz, CDC13) 8 = 7.32-7.26 (m, 1H), 7.22-7.15 (m, 1H), 3.90 (s, 3H)
ppm.
MS (En; M+=205, 207
23-C: tert-Butyl 4-(6-fluoro-5-methoxypyridin-2-yl)-4-h~ypiperidine-
10 1-carboxylate
The title compound was prepared according to the procedure described in
Example 18 from 6-bromo-2-fluoro-3-methoxypyridine: 948 mg (49%) as a
colorless oil.
1H NMR (300MHz, CDCl3) ~ = 7.31 (dd, J=9.9, 8.3Hz, 1H), 7.18 (dd, J=8.3, 0.9
15 Hz, 1H), 4.15-3.95 (m, 2H), 3.91 (s, 3H), 3.32-3.15 (m, 2H), 2.02-1.80 (m,
2H),
1.70-1.53 (m, 2H), 1.48 (s, 9H) ppm.
23-C: 4-(6-Fluoro-5-methoxypyridin-2-~piperidin-4-of dihydrochloride
The title compound was prepared according to the procedure described in
Example 18 from tert-butyl 4-(6-fluoro-5-methoxypyridin-2-yl)-4-
20 hydroxypiperidine-1-carboxylate: 623 mg (72%) as a white solid.
1H NMR (300MHz, DMSO-d6) 8 = 9.24-9.12 (m, 1H), 8.78 (br.s, 1H), 7.69 (dd,
J=10.6, 8.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 5.74 (br.s, 1H), 3.88 (s, 3H),
3.20-3.10
(m, 4H), 2.30-2.16 (m, 2H), 1.80-1.66 (m, 2H) ppm.
MS (ESA; (M+H)+ = 227.01
25 23-D: 2-~4-(6-Fluoro-5-methoxypyridin-2-yl)-4-hydroxypiperidin-1-yll-1-
{ 3-methyl-4-f (triisoprop~yl)oxylphenyl ~ ethanone
The title compound was prepared according to the procedure described in
Example CJ-26562-27 from 2-bromo-1-{3-methyl-4-[(triisopropylsilyl)oxyphenyl]-
ethanone and 4-(6-fluoro-5-methoxypyridin-2-yl)piperidin-4-of dihydrochloride:
699
3~ mg (quant.) as a yellow solid.
1H NMR (270 MHz, DMSO-d6) 8 = 7.85-7.80 (m, 2H), 7.66-7.47 (m, 2H), 6.88 (d,
J--8.9 Hz, 1H), 5.03 (s, 1H), 3.85 (s, 3H), 3.73 (s, 2H), 2.67-2.50 (m, 4H),
2.24 (s,
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3H), 2.20-1.98 (m, 2H), 1.51-1.25 (m, 5H), 1.08 (d, J--7.2 Hz, 18H) ppm.
MS (ESI); (M+H)+ = 531.28
23-E: 4-(6-Fluoro-5-methoxypyridin-2-yl)-1-(2-hydroxy-2-f 3-meth-4-
j(triisopropylsilyl)oxylphen l~yl)piperidin-4-of
The title compound was prepared according to the procedure described in
Example CJ-26562-27 from 2-[4-(6-fluoro-5-methoxypyridin-2-yl)-4-
hydroxypiperidin-1-yl]-1-{ 3-methyl-4-[(triisopropylsilyl)oxy]phenyl }
ethanone: 649
mg (94%) as a yellow solid.
1H NMR (270 MHz, DMSO-d6) S = 7.66-7.58 (m, 1H), 7.49 (d, J--7.9 Hz, 1H), 7.12
(s, 1H), 7.04 (d, J--8.2 Hz, 1H), 6.72 (d, J--8.2 Hz, 1H), 4.98 (s, 1H), 4.75
(s, 1H),
4.60 (br.s, 1H), 3.85 (s, 3H), 2.71-2.01 (m, 8H), 2.18 (s, 3H), 1.50-1.44 (m,
ZH),
1.35-1.20 (m, 3H), 1.07 (d, J--7.2 Hz, 18H) ppm.
MS (ESI); (M+H)+ = 533.29
23-F: 4-(6-Fluoro-5-methoxypyridin-2-yl)-1-f2-h~y-2-(4-h dery-3-
methylphenyl)ethyllpiperidin-4-of
By the procedures of example 2, 4-(6-fluoro-5-methoxypyridin-2-yl)-1-(2-
hydroxy-2-{ 3-methyl-4-[(triisopropylsilyl)oxy]phenyl } ethyl)piperidin-4-of
was
converted to the title compound obtained as a white solid in 60% (291 mg)
after
rerystallization from 2-propanol.
1H NMR (270 MHz, DMSO-d6) 8 =9.08 (s, 1H), 7.66-7.58 (m, 1H), 7.49 (d,
J--8.lHz, 1H), 7.02 (s, 1H), 6.94 (d, J--8.1 Hz, 1H), 6.69 (d, J--8.1 Hz, 1H),
4.99 (s,
1H), 4.63 (s, 1H), 4.55 (s, 1H), 3.86 (s, 3H), 2.76-2.66 (m, 2H), 2.54-2.30
(m, 4H),
2.10 (s, 3H), 2.12-1.96 (m, 2H), 1.50-1.44 (m, 2H) ppm.
MS (ESI); (M+H)+ = 377.13, (M-H)- = 375.20
m.p.172.3°C
IR (KBr); 3382, 3317 crri 1
Example 24
1-[2-Hvdroxy-2-(4-hvdroxv-3-methvlnhenvl)ethvll-4-(6-nronoxvnvridin-3
~piperidin-4-of
24-A: 5-Bromo-2-propoxypyridine
To a stirred solution of sodium (591 mg, 24.6 mmol) in 2-propanol (20 mL)
was added a solution of 5-bromo-2-nitropyridine (5 g, 24.6 mmol) in 2-propanol
(10
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77
mL) at room temperature and the mixture was stirred under reflux for 2.5
hours.
After all solvents were removed, the residue was diluted with dichloromethane
and
H20, and extracted with dichloromethane. The combined organic layer was dried
and evaporated. The residue was purified by chromatography on silica gel,
eluting
with ethyl acetate / hexane (1:10, v/v), to afford the titled compound as a
colorless
oil (3.84 g, 72 %).
1H NMR (270MHz, CDC13) 8 = 8.17 (d, J=2.6 Hz, 1H), 7.63 (dd, J=8.7, 2.6 Hz,
1H), 6.64 (d, J=8.7 Hz, 1H), 4.21 (t, J=6.6 Hz, 2H), 1.84-1.70 (m, 2H), 1.01
(t,
J=7.4 Hz, 3H) ppm.
MS (En; M+ = 215, 217
24-B: tart-But~ydroxy-4-(6-propoxypyridin-3-~piperidine-1-
carboxylate
The title compound was prepared according to the procedure described in
Example 18 from 5-bromo-2-propoxypyridine: 2.57 g (75%) as a yellow oil.
1H NMR (270MHz, CDCl3) ~ = 8.23 (d, J=2.6 Hz, 1H), 7.68 (dd, J=8.7, 2.6 Hz,
1H), 6.72 (d, J=8.7 Hz, 1H), 4.24 (t, J=6.8 Hz, 2H), 4.00 (br.s, 2H), 3.29-
3.19 (m,
2H), 2.04-1.70 (m, 6H), 1.48 (s, 9H), 1.02 (t, J=7.4 Hz, 3H) ppm.
MS (E~; M+= 336
24-C: 4-(6-Propoxypyridin-3-~piperidin-4-of dihydrochloride
The title compound was prepared according to the procedure described in
Example 18 from tart-butyl 4-hydroxy-4-(6-propoxypyridin-3-yl)piperidine-1-
carboxylate: 2.5 g (quant.) as a yellow solid.
1H NMR (300MHz, DMSO) b = 9.35-9.00 (m, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.94
7.80 (m, 1H), 7.02-6.88 (m, 1H), 4.60-4.00 (m, 4H), 3.22-3.10 (m, 4H), 2.32-
2.15
(m, 2H), 1.83-1.76 (m, 2H), 1.77-1.66 (m, 2H), 0.96 (t, J = 6.8 Hz, 3H) ppm.
MS (En; M+=236
24-D: 2-f4-Hydroxy-4-(6-propoxypyridin-3-~piperidin-1-yll-1-~ 3-
methyl-4-f(triisoprop~ l~ylphenyllethanone
The title compound was prepared according to the procedure described in
Example CJ-26562-27 from 2-bromo-1-{ 3-methyl-4-[(triisopropylsilyl)oxyphenyl]
ethanone and 4-(6-propoxypyridin-3-yl)piperidin-4-of dihydrochloride: 716 mg
(quant.) as a brown oil.
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1H NMR (270 MHz, DMSO-d6) 8 = 8.23-8.18 (m, 1H), 7.85-7.74 (m, 3H), 6.88 (d,
J--8.2 Hz, 1H), 6.73 (d, J--8.6 Hz, 1H), 4.88 (s, 1H), 4.18 (t, J--6.6 Hz,
2H), 3.77 (s,
2H), 3.10-2.50 (m, 4H), 2.24 (s, 3H), 1.99-1.58 (m, 5H), 1.38-1.17 (m, 3H),
1.08 (d,
J--7.4 Hz, 18H), 0.95 (s, 3H) ppm.
MS (ESA; (M+H)+ = 541.31
24-E: 1-(2-Hydroxy-2-~3-methyl-4-~(triisopropylsilyl)oxylphenyl~eth l~-4-
(6-propoxypyridin-3-yl)piperidin-4-of
The title compound was prepared according to the procedure described in
Example CJ-26562-27 from 2-[4-hydroxy-4-(6-propoxypyridin-3-yl)piperidin-1-yl]
1-{3-methyl-4-[(triisopropylsilyl)oxy]phenyl}ethanone: 666 mg (94%) as a
yellow
oil.
1H NMR (270 MHz, DMSO-d6) ~ = 8.21 (d, J--2.1 Hz, 1H), 7.76 (dd, J--8.7, 2.1
Hz,
1H), 7.07 (d, J--8.6 Hz, 1H), 7.12 (s, 1H), 6.75-6.70 (m, 2H), 4.84 (s, 1H),
4.65-4.58
(m, 2 H), 4.18 (t, J--6.8 Hz, 2H), 2.99-2.35 (m, 6H), 2.18 (s, 3H), 1.95-1.57
(m, 6H),
1.37-1.20 (m, 3H), 1.07 (d, J=7.2 Hz, 18H), 0.95 (t, J=7.4 Hz, 3H) ppm.
MS (ESn; (M+H)+ = 543.32
24-F: 1-f 2-Hydroxy-2-(4-h, day-3-meth~phenyl)ethyll-4-(6-
propoxypyridin-3-yl)-piperidin-4-of
By the procedures of example 2, 1-(2-hydroxy-2-{3-methyl-4
[(triisopropylsilyl)oxy]phenyl}ethyl)-4-(6-propoxypyridin-3-yl)piperidin-4-of
was
converted to the title compound obtained as a white solid in 40% (200 mg)
after
crystallization from 2-propanol.
1H NMR (270 MHz, DMSO-d6) 8 = 9.08 (s, 1H), 8.21 (br.s, 1H), 7.76 (d, T--9.4
Hz,
1H), 7.02 (s, 1H), 6.95 (d, J=9.4 Hz, 1H), 6.73 (d, J--9.4 Hz, 1H), 6.70 (d, J-
-9.4 Hz,
1H), 4.84 (s, 1H), 4.65 (s, 1H), 4.56 (br.s, 1H), 4.18 (t, J--6.4 Hz, 2H),
2.75-2.30 (m,
6H), 2.10 (s, 3H), 1.95-1.85 (m, 2H), 1.75-1.54 (m, 4H), 0.95 (t, J--7.2 Hz,
3H) ppm.
MS (ESn; (M+H)+ = 387.16, (M-H)- = 385.25
m.p. 187.4°C
IR (KBr); 3319, 1611 cm 1
Example 25
1-[2-(3-chloro-4-h d~yphen l~ydroxyethyll-4-(6-methoxypyridin-3-
~piperidin-4-of hydrochloride
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25-A: 1~2-f4-(benz~y)-3-chlorophenyll-2-h d~~yl~-4-(6-
methoxypyridin-3-yl)piperidin-4-of
To a stirred suspention of 4-(6-methoxypyridin-3-yl)piperidin-4-of
dihydrochloride
(0.86g) in tetrahydrofuran (10 ml) was added triethylamine (l.5mL) at room
temperature under nitrogen. then tetrahydrofuran solution of 1-[4-(benzyloxy)-
3
chlorophenyl]-2-bromoethanone (J. Med. Chem., 23 738 (1980)) (0.73g)was added
to the mixture. The whole was stirred at room temperature 3 hours. The
reaction
mixture was added ethyl alcohol (5 mL) and sodium borohydride (0.5g).
The mixture was stirred 3 hours and poured into water (100 ml) whole was
extracted with ethyl acetate (50 mL x2). The combined organic layers were
washed with saturated aqueous sodium chloride solution, dried over sodium
sulfate,
filtered and concentrated under reduced pressure. The residue was purified by
chromatography on amino type silica gel, eluting with ethyl acetate / methanol
(20:1
v/v), to afford the titled compound as a solid (0.6 g).
1H NMR (300 MHz, CDCl3) 8 8.03 (d, J = 2 Hz, 1H), 7.72 (dd, J-- 9, 2 Hz, 1H),
7.48-7.28 (m, 6H), 7.19 (dd, J-- 9, 2 Hz, 1H), 6.94 (d, J = 8 Hz, 1H), 6.75
(d, J = 9
Hz, 1H), 5.16 (s, 2H),4.68 (dd, J-- 10,42 Hz, 1H), 3.02 (brd, J = 12 Hz, 1H),
2.83 (dt,
J-- 2, 12 Hz, 1H), 2.74-2.66 (1H), 2.60-2.43 (m, 3H), 2.21-2.04 (m, 2H), 1.88-
1.76
(m, 2H) ppm.
25-B: 1-f2-(3-chloro-4-h d~roxyphen l~ d~yeth~l-4-(6-
methoxypyridin-3-yl)piperidin-4-of hydrochloride
A mixture of 1-{2-[4-(benzyloxy)-3-chlorophenyl]-2-hydroxyethyl}-4-(6-
methoxypyridin-3-yl)piperidin-4-of (0.6g), palladium 5 wt% on activated carbon
(0.04g) and methanol(50mL) was stirred under hydrogen atmosphere (4kg/m2 ) at
room temperature for 5 hours. The resulting mixture was filtered through
Celite, and
the filtrate was concentrated. The residue was purified by chromatography on
amino
type silica gel, eluting with methyl alcohol / ethyl acetate (1:20 v/v), to
afford the
titled compound as a white solid (0.45 g). Hydrogen chloride (0.27 ml, l.0eq),
4.0 M
solution in ethyl acetate, was added to a solution of 1-[2-(3-chloro-4-
hydroxyphenyl)-2-hydroxyethyl]-4-(6-methoxypyridin-3-yl)piperidin-4-of (0.6 g)
in
methyl alcohol (5 mL). The mixture was stirred for 1 hours at room temperature
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and concentrated in vacuo.. The residue was crystallized from 2-propanol to
afford
the titled compound as a white solid. (0.22 g).
1H NMR (300 MHz, DMSO-d6) b = 10.28 (s, 1H), 9.71 (br, 1H), 8.25 (d, J = 2 Hz,
1H), 7.76 (dd, J = 9, 2 Hz, 1H), 7.41 (d, J = 2 Hz, 1H), 7.21 (dd, J = 8, 2
Hz, 1H),
5 7.00 (d, J= 8 Hz, 1H), 6.84 (d, J= 9 Hz, 1H), 6.24-6.21 (br, 1H), 5.57 (br,
2H), 5.1-
5.0 (br, 1H), 3.84 (s, 3H), 3.7-3.2 ( 4H), 2.5-2.3 (2H), 2.0-1.8 (m, 2H) ppm
MS (ESI]; (M+H)+ = 379.05, (M-H)- = 377.13
m.p. 214.3°C
Example 26
10 1-~2-(3-chloro-4-hydroxyphen l~ d~~yl1-4-f4-
(methoxymethyl)phen~piperidin-4-of hydrochloride
26-A: 1-~4-(benzyloxy)-3-chlorophenyll-2-~4-hydroxy-4-f4-
L ethox~yl)phenyllpiperidin-1-yl ~ ethanone
To a stirred solution of 4-[4-(methoxymethyl)phenyl]piperidin-4-of (0.65g) in
15 tetrahydrofuran (5 ml) was added triethylamine (2.6g) at room temperature
under
nitrogen atmosphere and tetrahydrofuran solution of 1-[4-(benzyloxy)-3-
chlorophenyl]-2-bromoethanone (0.7g). Whole was stirred at room temperature 16
hours. The reaction mixture was added water and extracted with ethyl acetate.
The
organic layer was washed with brine and dried over NaS04. The residue was
20 concentrated in vacuo to afford the titled compound as a solid (0.7g). The
crude
product was used in the next step without further purification.
26-B: 1-~ 2-~4-(benz~y)-3-chlorophenyll-2-hydroxyethyl }-4-~4-
(methox meth~phen ~~llpiperidin-4-of
The title compound is prepared from 1-[4-(benzyloxy)-3-chlorophenyl]-2-{4-
25 hydroxy-4-[4-(methoxymethyl)phenyl]piperidin-1-yl}ethanone (0.7g) inseared
of 1-
{ 2-[4-(benzyloxy)-3-chlorophenyl]-2-hydroxyethyl }-4-(6-methoxypyridin-3-
yl)piperidin-4-of according to the method described in Example 1 as a solid
(0.65g).
1H NMR (300 MHz, CDC13) S = 7.52-7.3 (m, 10H), 7.20 (dd, J-- 9, 2 Hz, 1H),
6.94
(d, J--9 Hz, 1H), 5.16 (s, 2H), 4.73 (dd, J--10, 4 Hz, 1H), 4.46 (s, 2H), 3.40
(s, 3H),
30 3.12-3.05 (m, 1H), 2.94-2.75 (m, 2H), 2.70-2.45 (m, 2H), 2.31-1.76 (m, 5H)
ppm.
26-C: 1-[2-(3-chloro-4-hydroxy~henyl)-2-hydroxyethyll-4-f 4-
(methoxymethyl)phenyllpiperidin-4-of hydrochloride
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The title compound is prepared from 1-{ 2-[4-(benzyloxy)-3-chlorophenyl]-2-
hydroxyethyl}-4-[4-(methoxymethyl)phenyl]piperidin-4-of (0.5g) inseared of 1-
[4-
(benzyloxy)-3-fluorophenyl]-2-[4-hydroxy-4-(6-methoxypyridin-3-yl)piperidin-1-
yl]ethanone according to the method described in Example 25 as a solid
(0.17g).
1H NMR (300 MHz, CDC13) S = 7.50 (d, J = 8 Hz, 2H), 7.39 (d, J = 8 Hz, 2H),
7.35
(d, J = 8 Hz, 2H), 7.18 (dd, J = 8, 2 Hz, 1 H), 6.98 (d, J = 8 Hz, 1 H), 4.69
(dd, J =
11,3 Hz, 1H), 4.46 (s, 2H), 3.40 (s, 3H), 3.02 (d, J = 11 Hz, 1H), 2.85 (dt, J
= 3, 12
Hz, 1H), 7.77 (d, J = 11 Hz, 1H), 2.61-2.35 (m, 3H), 2.25-2.08 (m, 2H), 1.85-
1.75
(m, 2H) ppm.
M~ (EEI); (M+H)+= 358.10, (M-H)-= 356.20
m.p. 182.3°C
Example 27
1-f2-(2,5-difluoro-4-h droxyphenyl)-2-h d~yethyll-4-(3-fluorophenyl)~peridin-4-
ol
27-A: 1-(2,5-difluoro-4-hydroxyphenyl)ethanone
To a stirred suspension of alminium trichloride (43.7 g) in carbon disulfide
(100 mL) was added chloroacetyl chloride (16.1g) at room remperature, and the
mixture was stirred for 1 hour. A solution of 2,5-difluorophenol (21.3 g) in
carbon
disulfide (50 mL) was added to the mixture. Whole was stirred under reflux for
16
hours and cooled to room temperature. The resulting mixture was poured onto
ice-
water and extracted with ethyl acetate. The combined organic layer was washed
with water and brine, dried (sodium sulfate) and evaporated. The residue was
purified by chromatography on silica gel, eluting with ethyl acetate / n-
hexane (1:4
v/v), to afford the titled compound as a solid (21.5 g).
IH NMR (300 MHz, CDC13) S = 8.67 (dd, J = 11, 7 Hz, 1H), 6.78 (dd, J = 11, 7
Hz,
1H), 6.21 (br, 1H), 2.60 (d, J = 5 Hz, 3H) ppm.
27-B: 1-( 2,5-difluoro-4-[(triisoprop~lyl)ox~lphenyl ~ ethanone
The title compound was prepared according to the procedure described in
Example 2 from 1-(2,5-difluoro-4-hydroxyphenyl)ethanone (8.1 g) as a colorless
oil.
1H NMR (300 MHz, CDCl3) ~ = 7.63 (dd, J = 1 l, 7 Hz, 1H), 6.68 (dd, J = 12, 7
Hz,
1H), 2.59 (d, J= 5 Hz, 3H), 1.85-1.25 (m, 3H), 1.11 (d, J= 7 Hz, 18H) ppm.
27-C: 2-bromo-1-[ 2,5-difluoro-4-f (triisopropylsilyl)oxy]_~he~l ~ ethanone
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The title compound was prepared according to the procedure described in
Example 4 from 1-{2,5-difluoro-4-[(triisopropylsilyl)oxy]phenyl}ethanone (12
g) as
oil.
1H NMR (300 MHz, CDCl3) 8 = 7.69 (dd, J = 11, 7 Hz, 1H), 6.70 (dd, J = 12, 7
Hz,
1H), 4.47 (d, J= 3 Hz, 2H), 1.36-1.20 (m, 3H), 1.11 (d, J= 7 Hz, 18H) ppm.
27-D: 1-(2-( 2,5-difluoro-4-f (triisopropylsilyl)oxylphenyll-2-
hydrox~yl)-4-(3-fluorophen~piperidin-4-of
The title compound was prepared according to the procedure described in
Example
25 from 2-bromo-1-{2,5-difluoro-4-[(triisopropylsilyl)oxy]phenyl} ethanone
(0.8 g)
and 4-(3-fluorophenyl)piperidin-4-of as a solid.The crude product was used in
the
next step without further purification.
27-E: 1-f2-(2,5-difluoro-4-h~y~hen l~ydrox~yll-4-(3-
fluorophenyl)piperidin-4-of
The title compound was prepared according to the procedure described in
Example
2 from 1-(2-{2,5-difluoro-4-[(triisopropylsilyl)oxy]phenyl}-2-hydroxyethyl)-4-
(3-
fluorophenyl)piperidin-4-of (0.8 g) as a solid (0.4g).
1H NMR (300 MHz, CDC13) S = 7.38-7.21 (m, 4H), 6.97 (t, J = 7 Hz, 1H), 6.69
(dd,
J = 11, 7 Hz, 1H), 5.02 (d, J = 10 Hz, 1H), 3.06 (d, J = 12 Hz, 1H), 2.90-2.40
(m,
5H), 2.15 (dq, J= 5, 13 Hz, 2H), 1.82-1.75 (m, 2H) ppm.
27-F: 1-[2-(2,5-difluoro-4-h droxyphenyl)-2-hydroxyethyll-4-(3-
fluorophen~piperidin-4-of hydrochloride
Hydrogen chloride (0.27 ml, l.Oeq), 4.0 M solution in ethyl acetate, was
added to a solution of 1-[2-(2,5-difluoro-4-hydroxyphenyl)-2-hydroxyethyl]-4-
(3-
fluorophenyl)piperidin-4-of (0.4 g) in methyl alcohol (5 mL). The mixture was
stirred for 1 hours at room temperature and concentrated in vacuo.. The
residue
was crystallized from 2-propanol-diisopropylether to afford the titled
compound as a
white solid. (0.2 g).
1H NMR (300 MHz, DMSO-d6) 8 = 10.53 (br, 1H), 10.06 (br, 1H), 7.47-7.24(m,
4H), 7.10 (t, J = 9 Hz, 1H), 6.83 (dd, J = 11, 7 Hz, 1H), 6.29 (br, 1H), ppm
*other
proton signals were couldn't read for the broadening of peak.
MS (ESI]; (M+H)+ = 368.01, (M-H)- = 365.97
m.p. 207.0°C
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Example 28
1-f 2-(2,5-difluoro-4-hydroxynhenyl)-2-hydroxyethyll-4-(6-methoxypyridin-3-
~piperidin-4-of
28-A: 1-(2-~2,5-difluoro-4-((triisopropylsilyl)ox~ henyl}-2-
h~~yl)-4-(6-methoxypyridin-3-yl)piperidin-4-of
The title compound was prepared according to the procedure described in
Example
25 from 2-bromo-1-{ 2,5-difluoro-4-[(triisopropylsilyl)oxy]phenyl } ethanone
(0.8 g)
as a solid (0.38 g). The crude product was used in the next step without
further
purification.
28-B: 1-~2-(2,5-difluoro-4-hydroxyphenyl)-2-h d~~yll-4-(6-
methoxypyridin-3-~piperidin-4-of hydrochloride
The title compound is prepared from 1-(2-{2,5-difluoro-4-
[(triisopropylsilyl)oxy]phenyl }-2-hydroxyethyl)-4-(6-methoxypyridin-3-
yl)piperidin-
4-0l (0.38g) inseared of -(2-{2,5-difluoro-4-[(triisopropylsilyl)oxy]phenyl}-2-
hydroxyethyl)-4-(3-fluorophenyl)piperidin-4-of according to the method
described
in Example 27 as a solid (0.16g).
1H NMR (300 MHz, DMSO-d6) ~ = 10.58 (br, 1H), 10.01 (br, 1H), 8.25 (d, J = 2
Hz~
1H), 7.74 (dd, J = 9, 3 Hz, 1H), 7.26 (dd, J = 7, 12 Hz, 1H), 6.9-6.7 (m, 2H),
5.29 (d,
J= 8 Hz, 1H), 3.85 (s, 3H), 3.6-3.5 (m, 2H), 3.43-3.20 (m, 4H), 2.5-2.3 (2H),
1.84 (t,
J = 14 Hz, 2H) ppm
MS (ESn; (M+H)+ = 381.02, (M-H)- = 378.96
m.p. 199.5°C
Example 29
1-(2-(2-chloro-4-hydroxyphen l~ydroxyethyll-4-(6-methoxy~yridin-3-
~piperidin-4-of
29-A: 1- ( 2-chloro-4-~(triisoproRylsilyl)oxylphenyl } ethanone
The title compound was prepared according to the procedure described in
Example 2 from 1-(2,-chloro-4-hydroxyphenyl)ethanone (10.8 g) as a colorless
oil.
1H NMR (300 MHz, CDCl3) 8 = 7.61 (d, J= 9 Hz, 1H), 6.92 (d, J= 2 Hz, 1H), 6.79
(dd, J= 9, 2 Hz, 1H), 2.63 (s, 3H), 1.32-1.20 (m, 3H), 1.10 (d, J= 7 Hz, 18H)
ppm.
29-B: 2-bromo-1-}2-chloro-4-~(triiso~rop lsilyl)ox l~phenyl}ethanone
The title compound was prepared according to the procedure described in
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Example 4 from 1-{2-chloro-4-[(triisopropylsilyl)oxy]phenyl}ethanone (13 g) as
oil.
1H NMR (300 MHz, CDC13) 8 = 7.63 (d, J = 9 Hz, 1H), 6.94 (d, J = 2 Hz, 1H),
6.83
(dd, J= 9, 2 Hz, 1H), 4.55 (s, 2H), 1.35-1.20 (m, 3H), 1.10 (d, J= 7 Hz, 18H)
ppm.
29-C: 1-(2-~2-chloro-4-[(triisoprop~yl)oxy~phen l~ydroxyethyl)-4-
(6-methoxypyridin-3- 1y )~iperidin-4-of
The title compound was prepared according to the procedure described in
Example
25 from 2-bromo-1-{2-chloro-4-[(triisopropylsilyl)oxy]phenyl}ethanone (0.8 g)
and
4-(6-methoxypyridin-3-yl)piperidin-4-of (0.55 g) as a solid (0.33 g).
1H NMR (300 MHz, CDCl3) b 8.30 (d, J= 2 Hz, 1H), 7.72 (dd, J-- 9, 2 Hz, 1H),
7.47 (d, J-- 8 Hz, 1H), 6.86 (d, J= 2 Hz, 1H), 6.82 (dd, J-- 8, 2 Hz, 1H),
6.75 (d, J=
9 Hz, 1H), 5.12 (dd, J-- 10, 3 Hz, 1H), 3.93 (s, 3H), 3.76-3.72 (m, 2H), 3.09
(brd, J
= 11 Hz, 1H), 2.86-2.53 (m, 3H), 2.35 (dd, J-- 10, 13 Hz, 1H), 2.19-2.06 (m,
2H),
1.90-1.77 (m, 2H), 1.30-1.18 (m, 3H), 1.09 (d, J = 7 Hz, 18H) ppm
29-D: 1-f2-(2-chloro-4-hydroxyphen l~ydroxyethyll-4-(6-
methoxypyridin-3-yl)~peridin-4-of
The title compound was prepared according to the procedure described in
Example
2 from 1-(2-{2-chloro-4-[(triisopropylsilyl)oxy]phenyl}-2-hydroxyethyl)-4-(6-
methoxypyridin-3-yl)piperidin-4-of (0.32 g) as a solid (0.16g).
1H NMR (300 MHz, DMSO-d6) ~ 9.73 (br, 1H), 8.24 (d, J= 3 Hz, 1H), 7.77 (dd, J--
9, 3 Hz, 1H), 7.39 (d, J-- 9 Hz, 1H), 6.77-6.73 (m, 3H), 5.01-4.97 (br, 2H),
4.86 (s,
1H), 3.83 (s, 3H), 2.8-2.47 (4H), 2.40 (brd, J = 6 Hz, 2H), 1.98-1.88 (m, 2H),
1.63-1.58 (m, 2H) ppm..
MS (ESn; (M+H)+ = 378.94, (M-H)- = 376.89
m.p. 190.5°C
